Amphiphilic molecular modules and constructs based thereon

ABSTRACT

The present invention relates to the preparation of synthons that are used to form modules that, in turn, are used to form two-dimensional close-packed planar arrays, referred to as nanomembranes. In a presently preferred embodiment, a nanomembrane herein constitutes a filter.

FIELD OF THE INVENTION

[0001] This invention is related to the fields of organic chemistry andnanotechnology. In particular, it relates to materials and methods forthe construction of amphiphilic modules and the formation ofnanomembranes, from the modules.

BACKGROUND OF THE INVENTON

[0002] In 1959, Richard Feynman addressed a meeting of the AmericanPhysical Society with a talk titled “There's Plenty of Room at theBottom.” Professor Feynman, drawing on his own fascination with biology(“Biological systems can be exceedingly small . . . but they are active;they manufacture substances, they walk around; . . . and they do allkind of marvelous things—all on a very small scale.”), predicted thatamazing feats of man-made miniaturization would be realized in the nottoo distant future.

[0003] Twenty-six years later, K. Eric Drexler wrote a book entitled“Engines of Creation” in which he described nanotechnology as “theknowledge and means for designing, fabricating and employing molecularscale devices by the manipulation and placement of individual atoms andmolecules with precision on the atomic scale.”

[0004] In 1990, Donald Eigler, working in the IBM Almaden ResearchCenter, used the then recently developed scanning probe microscope (SPM)to manipulate 35 individual xenon atoms into the letters IBM on thesurface of a crystal of nickel. Since that time a tremendous amount ofeffort has been, and continues to be, spent on devising practicalapplications for this new-found ability to work directly with the atom.

[0005] In organic chemistry, the quest has not been so much to work withindividual atoms as to work with small groups of atoms—molecules—and usethem to build, under totally controlled conditions, multimoleculararchitectures capable of performing, on a submicroscopic scale,functions normally reserved for large-scale constructs. For example,rotaxanes and polyrotaxanes, molecules that are interlocked but notchemically bound to one another, exhibit some mechanicalcharacteristics—they act like micro-machines—are being widely studied.Likewise, dendrimers, mono-dispersed macromolecules with a regular andhighly branched three-dimensional architecture, also are receivingsubstantial attention, especially in the area of catalysis. Carbonnanotubes, isolated from the carbon soot on graphite electrodes, haveelicited a tremendous amount of interest for a wide range ofapplications such as strength enhancing fillers for conventionalpolymers, fuel cell construction, electrical field emitters and quantumwires.

[0006] The use of biological processes is also being studied as anapproach to the assembly of non-biological nano-devices. For example, in1995, U.S. Pat. No. 5,468,851, entitled “Construction of GeometricalObjects from Polynucleotides,” was issued to Seeman and Zhang. Theinventors claimed the ability to produce “ . . . almost any structureone can imagine . . . ” starting with a double stranded polynucleotidesegment having a loop at one end that contains a restriction site. Theloop is cleaved at the restriction site, and another double strandedpolynucleotide segment, itself having a loop containing an endonucleaserecognizable sequence different from that of the first segment, isligated to the first segment at the cleavage site. The loop of thesecond segment is then cleaved and a third polynucleotide segment isligated into the system. The process is continued until the desiredstructure is achieved.

[0007] The formation of monomolecular thick, selectively permeablemembranes was described in 1997 by Hendel, et al., JACS, 1997,119:6909-18. Hendel and his coworkers reported the synthesis ofcalix[6]arenes and their deposition as Langmuir-Blodgett films on aporous poly[1 (trimethylsilyl)-1-propyne] substrate. They found that,when the calixarenes were positioned on the substrate such thatindividual calixarene molecules exactly spanned a pore in the substrate,a selectively permeable membrane was formed; i.e., nitrogen was found topass through the membrane about 10,000 times more slowly than helium.

[0008] Another approach to the synthesis of molecular scale constructswas patented in 1999 by Michl, et al. (U.S. Pat. No. 5,876,830). Michlanalogized his approach to the children's construction toy “TINKERTOY™”(Playskool, Inc., Pawtucket, R.I.). That is, Michl builds macromolecularstructures by linking together complex molecular modules usingconnectors, spacers, binders, etc. The procedure requires adheringmodules to a surface and then reacting connector groups on adjacentmodules with molecular “rods” to form monomolecular grids or nets.

[0009] In 2001, an international patent application, WO 01/27028 A1, toSpencer and Allis and entitled “Design and Fabrication of MolecularNanosystems,” published. There, Spencer and Allis describe structuralsub-units they term “synthons” which they claim can be used for thedesign and manufacture of molecular nanostructures, machines anddevices. Their synthons are rigid polyhedral structures, namelyclosocarboranes, which were selected based on their syntheticavailability and the fact that they exhibit the requisite substitutionalcontrol and structural diversity the inventors considered necessary forthe creation of nano-scale constructs.

[0010] For a further review of the above and other areas of research innanotechnology, see Chemical Reviews, 1999(7).

[0011] The present invention provides novel, extremely versatilemolecular modules, methods for their synthesis and fabrication intonanoscale devices, in particular selectively permeable membranes.

SUMMARY OF THE INVENTION

[0012] Thus, in one aspect, the present invention relates to anamphiphilic module, comprising 3-24 synthons independently selected fromthe group consisting of aryl, heteroaryl, alicyclic and heteroalicyclic,provided at least one of the synthons is different from the others. Thesynthons are arranged such that a first synthon is bonded to a secondsynthon through a linker, the second synthon is bonded to a thirdsynthon through a second linker, the third synthon is bonded to a fourthsynthon, if four synthons are desired in the module, the fourth to afifth, etc., until an nth synthon is bonded to its predecessor throughan (n−1)^(th) linker, where n is 4-24. The n^(th) synthon is then bondedto the first synthon through an nth linker to form a closed ring ofsynthons. There are also one or more lipophilic moieties bonded to oneor more of the synthons and one or more hydrophilic moieties bonded toone or more of the synthons.

[0013] In an aspect of this invention, each synthon is independentlyselected from the group consisting of benzene, naphthalene, anthracene,phenylene, phenathracene, pyrene, triphenylene, phenanthrene, pyridine,pyrimidine, pyridazine, biphenyl, bipyridyl, cyclohexane, cyclohexene,decaline, piperidine, pyrrolidine, tetrahydropyran, tetranhydrothiane,1,3-dioxane, 1,3-dithiane, 1,3-diazane, tetrahydrothiophene,tetrahydrofuran, pyrrole, cyclopentane, triptycene, adamantane,bicyclo[2.2.1]heptane, bicyclo[2.2.1]heptene,7-azabicyclo[2.2.1]heptane, 1,3-diazabicyclo[2.2.1]heptane,bicyclo[2.2.2]octane, bicyclo[2.2.2]octene, bicyclo[3.3.0]octane,bicyclo[3.3.1]nonane, bicyclo[3.3.1]nonene, bicyclo[4.2.2]decane orbicyclo[4.2.2]decene.

[0014] In a further aspect of this invention, the lipophilic moiety isselected from the group consisting of -(8C-28C)alkyl, —O(8C-28C)alkyl,—NH(8C-28C)alkyl, OC(O)-(8C--28C)alkyl, —C(O)O-(8C-28C)alkyl,—NHC(O)-(8C-28C)alkyl, —C(O)NH-(8C-28C)alkyl, —CH═CH-(8C-28C)alkyl and—C═-C-(8C-28C)alkyl. The carbon atoms of the (8C-28C)alkyl group may beinterrupted by one or more —S—, double bond, triple bond or —SiR′R″—groups, substituted with one or more fluorine atoms or any combinationof these. R′ and R″ independently comprise (1C-18C)alkyl.

[0015] In a still further aspect of this invention, the hydrophilicmoiety is selected from the group consisting of —OH, —OCH₃, —NH₂, —C≡N,—NO₂, —⁺NRR′R″, —SO₃ ⁻, —OPO₂ ²⁻, —OC(O)CH═CH₂, —SO₂NH₂, SO₂NRR′,—OP(O)(OCH₂CH₂N⁺RR′R″)O⁻, —C(O)OH, —C(O)O⁻, guanidinium, aminate,pyridinium, —C(O)OCH₃, —C(O)OCH₂CH₃, —C(O)OCH═CH₂, —O(CH₂)_(y)C(O)NH₂,—O(CH₂CH₂O)_(z)R′″ and

[0016] R, R′ and R″ are independently selected from the group consistingof hydrogen and (1 C-4C)alkyl, R′″ is selected from the group consistingof hydrogen, —CH₂C(O)OH and —CH₂C(O)NH₂. In the preceding groups, y is1-6 and z is 1-50.

[0017] In an aspect of this invention, each linker is independentlyselected from the group consisting of —O—, —S—, —NR¹⁷—, —SS—,—(CR¹⁷R¹⁸)_(m)—, —CH(OH)—, —C(OH)R¹⁷—CH₂N R¹⁸—, —C(OH)CH(NHR¹⁷)—,—CR¹⁷═CR¹⁸—, —C≡C—, —C(O)O—, —C(O)S—, —OC(O)O—, C(O)NR¹⁷—, —CR¹⁷═N—,—CR¹⁷═NNH—, —NHC(O)O—, —NHC(O)NR¹⁷—, —CH(OH)CH₂(CO₂R¹⁷) —,—CH═CR¹⁷C(O)—, —C≡C—C≡C—, —C(CH R¹⁷R¹⁸)S—,

[0018] —C(CH(CH₃)₂)Si(CH₃)₂—, —C(O)CH₂(CO₂R¹⁷)—, and

[0019] R¹⁷ and R¹⁸ are independently selected from the group consistingof hydrogen, (1C-4C)alkyl and a group that confers a selected chemicalor physical characteristic, or a combination thereof, on the module.

[0020] It is an aspect of this invention that, in the above amphiphilicmodules, every other synthon is the same; that the first, third, and ifpresent, fifth, seventh, etc., synthons are the same and the second, andif present, the fourth, sixth, eighth, etc., synthons are the same.

[0021] It is an aspect of this invention that, in the above amphiphilicmodules, all the linkers are the same.

[0022] An aspect of this invention is an amphiphilic module comprising12 synthons.

[0023] An aspect of this invention is an amphiphilic module comprising10 synthons.

[0024] An aspect of this invention is an amphiphilic module comprising 8synthons.

[0025] An aspect of this invention is an amphiphilic module comprising 6synthons.

[0026] An aspect of this invention is an amphiphilic module comprising 4synthons.

[0027] An aspect of this invention is an amphiphilic module of claim 1,comprising the formula:

[0028] A₁-A₈ are synthons. L₁-L₈ are linkers. One or more of R₁, R₃, R₅,R₇, R₉, R₁₁, R₁₃ and R₁₅ comprises a lipophilic group, which may be sameas, or different from, each of the other lipophilic groups. One or moreof R₂, R₄, R₆, R₈, R₁₀, R₁₂, R₁₄ and R₁₆ comprises a hydrophilic group,which may be the same as, or different from, each other hydrophilicgroup. Each R group that is not a lipophilic or a hydrophilic group isindependently either absent or comprises a group that confers a selectedchemical or physical characteristic or combination thereof on themodule. Each A and each L may also optionally be bonded to one or moreadditional substituents that confer selected chemical or physicalcharacteristics or combinations thereof on the module.

[0029] It is an aspect of this invention that, in the above amphiphilicmodule, A₁, A₃, A₅ and A₇ comprise the same synthon.

[0030] It is an aspect of this invention that, in the above amphiphilicmodule, A₂, A₄, A₆ and A₈ comprise the same synthon, which is differentfrom the A₁, A₃, A₅, A₇ synthon.

[0031] It is an aspect of this invention that, in the above amphiphilicmodule all the linkers are the same.

[0032] An aspect of this invention is an amphiphilic module, comprisingthe chemical structure:

[0033] X and Y are independently hydrogen, —OC(O)CH═CH₂, —NHC(O)CH═CH₂,

[0034] —SH or —NH₂. In the alternative, X can be —C(O)OH, —C(O)OCH₃,—C(O)Cl or another activated acid and Y is —NH₂, —OH or —SH. R₁ isselected from the group consisting of —CH₂—(10C-18C)alkyl,—CH═CH—(10C-18C)alkyl, —C≡C—(10C-18C)alkyl, —OC(O)-(10C-18C)alkyl,—C(O)O-(10C-18C)alkyl, —NHC(O)-(10C-18C)alkyl, —C(O)NH-(10C-18C)alkyland —O-(10C-18C)alkyl. One or more of R₂, R₃, R₄ and R₅ areindependently selected from the group consisting of hydrogen,—C(O)(CH₂)₂C(O)OCH₃, —C(O)CH═CH₂,

[0035] and

[0036] The subscript n1 is 1-50 and n2 is 1-4. At least one of R₂, R₃ orR₄ must be other than hydrogen. L is selected from the group consistingof —C(O)O—, —C(O)NH—, —CH₂NH— and —CH═N—, wherein the oxygen or nitrogenis bonded to either the benzene ring or the cyclohexyl ring.

[0037] In an aspect of this invention, the nitrogen or oxygen of the Lgroup is bonded to the cyclohexyl group in the above amphiphilic module.

[0038] In another aspect of this invention, the nitrogen or oxygen ofthe L group alternate around the ring. Thus, if a nitrogen or oxygen ofan L group is bonded to the cyclohexyl ring, the nitrogen or oxygen ofthe next L group going around the ring is bonded to the benzene ring.

[0039] An aspect of this invention is an amphiphilic module comprisingthe chemical structure:

[0040] Z is —NZ₁- or —CZ₂Z₃. Z₁ is selected from the group consisting ofhydrogen, an amino acid residue and —C(O)CH═CH₂. Z₂ is hydrogen and Z₃is selected from the group consisting of hydrogen, —OH, —NH₂ and —SH. Inthe alternative, one of Z₂ or Z₃ is selected from the group consistingof hydrogen, —OH, —NH₂, —SH, —(CH₂)_(z4)OH, —(CH₂)_(z4)NH₂ and—(CH₂)_(z4)SH and the other is selected from the group consisting of—(CH₂)_(z4)OH, —(CH₂)_(z4)NH₂ and —(CH₂)_(z4)SH, wherein Z₄ is 1, 2, 3or 4. R₁ is selected from the group consisting of CH₂-(10C-18C)alkyl,—CH═CH-(10C-18C)alkyl, —C≡C-(10C-18C)alkyl, —OC(O)-(10C-18C)alkyl,—C(O)O-(10C-18C)alkyl, —NHC(O)-(10C-18C)alkyl, —C(O)NH-(10C-18C)alkyland —O-(10C-18C)alkyl. One or more of R₂, R₃, R₄ and R₅ areindependently selected from the group consisting of hydrogen,—C(O)(CH₂)₂C(O)OCH₃, —C(O)CH═CH₂,

[0041] and

[0042] wherein n1 is 1-50 and n2 is 1-4. At least one of R₂, R₃ or R₄must be other than hydrogen. L is selected from the group consisting of—C(O)O—, —C(O)NH—, —CH₂NH— and —CH═N—, wherein the oxygen or nitrogen isbonded to either the benzene ring or the cyclohexane ring.

[0043] It is an aspect of this invention that, in the above amphiphilicmodule the nitrogen or oxygen of the L group is bonded to the cyclohexylring.

[0044] It is likewise an aspect of this invention that, in the aboveamphiphilic module, the nitrogen or oxygen of the L group alternatesaround the ring. Thus, if a nitrogen or oxygen of an L group is bondedto the cyclohexyl ring, the nitrogen or oxygen of the next L group goingaround the ring is bonded to the benzene ring.

[0045] An aspect of this invention is an amphiphilic module, comprisingthe chemical structure:

[0046] X and Y are independently hydrogen,

[0047] , —OC(O)CH═CH₂, —NHC(O)CH═CH₂, —SH or —NH₂. In the alternative, Xcan be —C(O)OH, —C(O)OCH₃, —C(O)Cl or another activated acid and Y is—NH₂, —OH or —SH. When X and Y are both hydrogen or —C(O)OCH₃, R₁ isselected from the group consisting of —CH═CH₂, —OC(O)CH═CH₂ and—NHC(O)CH═CH₂. When X and Y are both —SH or —NH₂ or X is —C(O)OCH₃ and Yis —NH₂, R₁ is hydrogen. R₆ is selected from the group consisting ofCH₂-(10C-18C)alkyl, —CH═CH-(10C-18C)alkyl, —C≡C-(10C-18C)alkyl,—OC(O)-(10C-18C)alkyl, —C(O)O-(10C-18C)alkyl, —NHC(O)-(10C-18C)alkyl,—C(O)NH-(10C-18C)alkyl and —O-(10C-18C)alkyl. One or more of R₂, R₃, R₄and R₅ are independently selected from the group consisting of hydrogen,—C(O)(CH₂)₂C(O)OCH₃, —C(O)CH═CH₂,

[0048] wherein n1 is 1-50 and n2 is 1-4. At least one of R₂, R₃ or R₄must be other than hydrogen. L is selected from the group consisting of—C(O)O—, —C(O)NH—, —CH₂NH— and —CH═N—, wherein the oxygen or nitrogen isbonded to either the benzene ring or the bicyclo[2.2.1]heptane ring.

[0049] In an aspect of this invention, in the above amphiphilic module,the nitrogen or oxygen of the L group is bonded to thebicyclo[2.2.1]heptane ring.

[0050] In an aspect of this invention, in the above amphiphilic module,the nitrogen or oxygen of the L group alternates around the ring. Thus,if a nitrogen or oxygen of an L group is bonded to thebicyclo[2.2.1]heptane ring, the nitrogen or oxygen of the next L groupgoing around the ring is bonded to the benzene ring.

[0051] An aspect of this invention is an amphiphilic module comprisingthe structure:

[0052] A₁-A₆ are the synthons. L₁-L₆ are the linkers. One or more of R₁,R₃, R₅, R₇, R₉ and R₁₁ comprises a lipophilic group, which may be sameas, or different from, each other. One or more of R₂, R₄, R₆, R₈, R₁₀and R₁₂ comprises a hydrophilic group, which may be the same as, ordifferent from, each other. Each R group that is not a lipophilic or ahydrophilic group is independently either absent or comprises a groupthat confer a selected chemical or physical characteristic orcombination thereof on the module. Each A and each L may optionally bebonded to one or more additional substituents that confer selectedchemical or physical characteristics or combinations thereof on themodule.

[0053] In an aspect of this invention, in the above amphiphilic module,A₁, A₃ and A₅ comprise the same synthon.

[0054] In an aspect of this invention, A₂, A₄ and A₆ in the aboveamphiphilic module also comprise the same synthon, which is differentfrom the A₁, A₃, A₅ synthon.

[0055] In an aspect of this invention, in the above amphiphilic module,all the linkers are the same.

[0056] An aspect of this invention is an amphiphilic module comprisingthe structure:

[0057] X and Y are both —SH or —NH₂. In the alternative, X is —C(O)OH,—C(O)OCH₃, —C(O)Cl or another activated acid and Y is —NH₂. R₁ isselected from the group consisting of —CH₂-(10C-18C)alkyl,—CH═CH-(10C-18C)alkyl, —C≡C-(10C-18C)alkyl, —OC(O)-(10C--18C)alkyl,—C(O)O-(10C-18C)alkyl, —NHC(O)-(10C-18C)alkyl, —C(O)NH-(10C-18C)alkyland —O-(10C-18C)alkyl. R₂, R₃ and R₄ are independently selected from thegroup consisting of hydrogen, —C(O)(CH₂)₂C(O)OCH₃, —C(O)CH═CH₂,

[0058] wherein n1 is 1-50 and n2 is 1-4. At least one of R₂, R₃ or R₄must be other than hydrogen. L is selected from the group consisting of—C(O)O—, —C(O)NH—, —CH₂NH— and —CH═N—, wherein the oxygen or nitrogen isbonded to either the benzene ring or the cyclohexyl ring.

[0059] In an aspect of this invention, in the above amphiphilic module,the nitrogen or oxygen of the L group is bonded to the cyclohexyl ring.

[0060] In a further aspect of this invention, in the above amphiphilicmodule the nitrogen or oxygen of the L group alternates around the ring.Thus, if a nitrogen or oxygen of an L group is bonded to the cyclohexylring, the nitrogen or oxygen of the next L group going around the ringis bonded to the benzene ring.

[0061] An aspect of this invention is an amphiphilic module, comprisingthe chemical structure:

[0062] X and Y are independently hydrogen,

[0063] —OC(O)CH═CH₂, —NHC(O)CH═CH₂, —SH or —NH₂. In the alternative, Xis —C(O)OH, —C(O)OCH₃, —C(O)Cl or another activated acid and Y is —NH₂,—OH or —SH. When X and Y are both hydrogen or —C(O)OCH₃, R₁ is selectedfrom the group consisting of —CH═CH₂, —OC(O)CH═CH₂ and —NHC(O)CH═CH₂.When X and Y are both —SH or —NH₂ or X is —C(O)OCH₃ and Y is —NH₂, R₁ ishydrogen. R₅ is selected from the group consisting ofCH₂-(10C-18C)alkyl, —CH═CH-(10C-18C)alkyl, —C≡C-(10C-18C)alkyl,—OC(O)-(10C-18C)alkyl, —C(O)O(10C--18C)alkyl, —NHC(O)-(10C-18C)alkyl,—C(O)NH-(10C-18C)alkyl and —O-(10C-18C)alkyl. R₂, R₃ and R₄ areindependently selected from the group consisting of hydrogen,—C(O)(CH₂)₂C(O)OCH₃, —CH₂C(O)CH═CH₂,

[0064] and

[0065] wherein n1 is 1-50 and n2 is 1-4. At least one of R₂, R₃ or R₄must be other than hydrogen. L is selected from the group consisting of—C(O)O—, —C(O)NH—, —CH₂NH— and —CH═N—, wherein the oxygen or nitrogen isbonded to either the benzene ring or the bicyclo[2.2.1]heptane ring.

[0066] In an aspect of this invention, in the above amphiphilic module,the nitrogen or oxygen of the L group is bonded to thebicyclo[2.2.1]heptane ring.

[0067] In another aspect of this invention, in the above amphiphilicmodule, the nitrogen or oxygen of the L group alternates around thering. Thus, if a nitrogen or oxygen of an L group is bonded to thebicyclo[2.2.1]heptane ring, the nitrogen or oxygen of the next L groupgoing around the ring is bonded to the benzene ring.

[0068] An aspect of this invention is an amphiphilic module, comprisingthe chemical structure:

[0069] X and Y are independently hydrogen,

[0070] , —OC(O)CH═CH₂, —NHC(O)CH═CH₂, —SH or —NH₂. In the alternative, Xis —C(O)OH, —C(O)OCH₃, —C(O)Cl or another activated acid and Y is —NH₂,—OH or —SH. R₁ is selected from the group consisting of—CH₂-(10C-18C)alkyl, —CH═CH-(10C-18C)alkyl, —C≡C-(10C-18C)alkyl,—OC(O)-(10C-18C)alkyl, —C(O)O-(10C-18C)alkyl, —NHC(O)-(10C-18C)alkyl,—C(O)NH-(10C-18C)alkyl and —O-(10C-18C)alkyl. R₂, R₃ and R₄ areindependently selected from the group consisting of hydrogen,—C(O)(CH₂)₂C(O)OCH₃, —C(O)CH═CH₂,

[0071] wherein n1 is 1-50 and n2 is 1-4. At least one of R ₂, R₃ or R₄must be other than hydrogen. L is selected from the group consisting of—C(O)O—, —C(O)NH—, —CH₂NH— and —CH═N—, wherein the nitrogen or oxygen isbonded to either the benzene ring or the cyclohexyl ring.

[0072] In an aspect of this invention, in the above amphiphilic module,the nitrogen or oxygen of the L group is bonded to the cyclohexyl ring.

[0073] In another aspect of this invention, in the above amphiphilicmodule, the nitrogen or oxygen of the L group alternates around thering. Thus, if a nitrogen or oxygen of an L group is bonded to thecyclohexyl ring, the nitrogen or oxygen of the next L group going aroundthe ring is bonded to the benzene ring.

[0074] An aspect of this invention is an amphiphilic module, comprisingthe chemical structure:

[0075] X and Y are independently hydrogen,

[0076] —OC(O)CH═CH₂, —NHC(O)CH═CH₂, —SH or —NH₂. In the alternative, Xis —C(O)OH, —C(O)OCH₃, —C(O)Cl or another activated acid and Y is —NH₂,—OH or —SH. When X and Y are both hydrogen or —C(O)OCH₃, R₁ is selectedfrom the group consisting of —CH═CH₂, —OC(O)CH═CH₂ and —NHC(O)CH═CH₂.When X and Y are both —SH or —NH₂ or X is —C(O)OCH₃ and Y is —NH₂, R₁ ishydrogen. R₅ is selected from the group consisting ofCH₂-(10C-18C)alkyl, —CH═CH-(10C-18C)alkyl, —C≡C-(10C-18C)alkyl,—OC(O)-(10C-18C)alkyl, —C(O)O-(10C-18C)alkyl, —NHC(O)-(10C-18C)alkyl,—C(O)NH-(10C-18C)alkyl and —O-(10C-18C)alkyl. R₂, R₃ and R₄ areindependently selected from the group consisting of hydrogen,—C(O)(CH₂)₂C(O)OCH₃, —C(O)CH═CH₂,

[0077] and

[0078] wherein n1 is 1-50 and n2 is 1-4. At least one of R₂, R₃ or R₄must be other than hydrogen. L is selected from the group consisting of—C(O)O—, —C(O)NH—, —CH₂NH— and —CH═N—, wherein the oxygen or nitrogen isbonded to either the benzene ring or the bicyclo[2.2.1]heptane ring.

[0079] In an aspect of this invention, in the above amphiphilic module,the nitrogen or oxygen of the L group is bonded to thebicyclo[2.2.1]heptane ring.

[0080] In a further aspect of this invention, in the above amphiphilicmodule, the nitrogen or oxygen of the L group alternates around thering. Thus, if a nitrogen or oxygen of an L group is bonded to thecyclohexyl ring, the nitrogen or oxygen of the next L group going aroundthe ring is bonded to the benzene ring.

[0081] Another aspect of this invention relates to a method ofsynthesizing an amphiphilic module. A plurality of a first synthoncomprising two functional groups that may be the same or different isprovided. A plurality of a second synthon, which is different than thefirst synthon, but also comprising two functional groups that may be thesame or different, is also provided. The functional groups of the firstsynthons are selected such that they can only react with the functionalgroups of the second synthons. The first and second synthons are thenput together in a solvent under conditions that cause the functionalgroups to react to form an amphiphilic module. The amphiphilic module isthen isolated.

[0082] In the above method, a reagent or reagents that catalyzes thereaction of the functional groups of the first synthon with thefunctional groups of the second synthon may be used.

[0083] A further aspect of this invention relates to an alternativemethod for preparing an Amphiphilic module. This method comprisesplacing a first synthon comprising a functional group in a solvent andthen adding a second synthon comprising a functional group that reactswith the functional group of the first synthon to form a dimer. Then athird synthon is added. The third synthon may be the same as, ordifferent from, the first synthon and comprises a functional group thatreacts with a second functional group of the second synthon to form atrimer. The preceding step is repeated until an n^(th) (n is 1-24)synthon is added. The n^(th) synthon comprises a functional group thatreacts with a second functional group of the first synthon to form aring.

[0084] In an aspect of this invention, a reagent or reagents may beadded to catalyze the reaction of a functional group of a synthon with afunctional group of the next synthon being added. In the alternative areagent may be added that reacts with a functional group of a synthon toform an intermediate, which then reacts with a functional group of thenext synthon that is added.

[0085] An aspect of this invention is a two-dimensional array comprisinga plurality of amphiphilic modules wherein each module is bonded to oneor more adjacent modules by one or more connectors between each pair ofadjacent modules.

[0086] In an aspect of this invention, in the above array, eachconnector is independently selected from the group consisting of —O—,—S—, —NR¹⁹—, —SS—, —(CR¹⁹R²⁰)_(m)—, —CH(OH)—, —C(OH)R¹⁹—CH₂NR²⁰—,—C(OH)CH(NHR¹⁹)—, —CR¹⁹═CR²⁰—, —C≡C—, —C(O)O—, —C(O)S—, —OC(O)O—,C(O)NR¹⁹—, —CR¹⁹═N—, —CR¹⁹═NNH—, —NHC(O)O—, —NHC(O)NR¹⁹—, —NHCH₂NH—,—NHC(NH)CH₂C(NH)NH—, —CH(OH)CH₂(CO₂R¹⁹)—, —CH═CR¹⁹C(O)—, —C≡C—C≡C—,—C(CHR¹⁹R²⁰)S—,

[0087] —C(CH(CH₃)₂)Si(CH₃)₂—, —C(O)CH₂(CO₂R¹⁹)—,

[0088] and an acrylate copolymer formed by reaction of a —OC(O)CH═CH₂group on each module and ethyl acrylate. R¹⁹ and R²⁰ are independentlyselected from the group consisting of hydrogen, (1C-4C)alkyl and a groupthat confers a selected chemical or physical characteristic, or acombination thereof.

[0089] In an aspect of this invention, in the above array, the connectoris separated from one or both of the modules by a spacer.

[0090] The spacer comprises a —(CH₂)_(n)— group, wherein n is 1-28, inanother aspect of this invention.

DETAILED DESCRIPTION OF THE INVENTION

[0091] Brief Description of the Tables

[0092] Table 1 is a list of functional groups that can react to form thepresently preferred linkers. The linkers formed are also shown.

[0093] Table 2 shows the results of quantum mechanical and molecularmechanical computations of the size of the pores formed from selectedsets of synthons and linkers.

[0094] Table 3 shows the results of quantum mechanical and molecularmechanical computations of the size of the pores formed by additionalsets of synthons and linkers.

[0095] Table 4 shows the results of experiments carried to determinewhat size ion can pass through a selected module of this invention.

BRIEF DESCRIPTION OF THE FIGURES

[0096] The figures are provided solely as visual aids in understandingthe present invention. They are not intended, nor should they beconstrued, to limit the scope of this invention in any mannerwhatsoever. For example, hexameric modules are used to exemplifyclose-packed arrays (FIG. 2A). Certain synthons are shown withfunctional groups that form connectors (FIGS. 2B and 2C). Certainfunctional groups, e.g., amino (—NH₂) groups are shown formingconnectors (FIG. 5). It is understood that other size modules, othersynthons and other functional groups could just as easily have been usedin the figures.

[0097] FIGS. 1A-1C show the structure of modules of this invention asdetermined by energy minimization computation.

[0098]FIG. 1A shows the structure of a tetramer module, essentially aparallelogram.

[0099]FIG. 1B shows the structure of a hexamer module, essentially anequilateral triangle.

[0100]FIG. 1C show the structure of an octamer module, essentially arhombus.

[0101]FIG. 2 depicts a close-packed two-dimensional array of hexamericmodules.

[0102]FIG. 2A shows the array without any connectors between modules.

[0103]FIG. 2B show the array with one connector between each pair ofadjacent modules.

[0104]FIG. 2C shows the array with two connectors between each pair ofadjacent modules.

[0105]FIG. 3 is a graph of a Languir isotherm demonstrating that themodules of this invention do form monomolecular Langmuir films.

[0106]FIG. 4 depicts some presently preferred connectors and thefunctional groups and reactants used for their formation.

[0107]FIG. 4A shows an imidate connector.

[0108]FIG. 4B shows an urea connector.

[0109]FIG. 4C shows a boronic acid amide connector.

[0110]FIG. 4D shows a copolymeric connector formed by the reaction ofacrylate functional groups on the synthons with external ethyl acrylate.

[0111]FIG. 5 depicts some additional presently preferred connectors.

[0112]FIG. 5A shows connectors formed when two functional groups arebonded to the same synthon in each module. In 5A, the connector is anaminal.

[0113]FIG. 5B shows the formation of disulfide connectors frommercaptans.

[0114]FIG. 5C shows the formation of cyclobutyl connectors by the [2+2]cycloaddition of acrylates on the synthons.

[0115]FIG. 5D shows a copolymeric connector formed by the reaction ofacrylate functional groups isolated from the synthons by seven methylenespacers with external ethyl acrylate.

[0116]FIG. 6 depicts the preparation of a nanomembrane. The figures arecartoon representations only and are not intended to depict an actualLangmuir-Blodgett trough.

[0117]FIG. 6A shows amphiphilic modules in chloroform which is floatingon a layer of water.

[0118]FIG. 6B shows the amphiphilic modules on the surface of the waterafter the chloroform has been evaporated.

[0119]FIG. 6C shows the amphiphilic modules compressed into aclose-packed array.

[0120]FIG. 6D shows the close-packed array in which connectors have beenformed between the amphiphilic modules.

DISCUSSION

[0121] As used herein, an “(nC-mC)alkyl, wherein n is 1 to 8 and m is 8to 28, refers to all alkyl groups comprising n to m carbon atoms. Forexample, a (1 C-4C)alkyl refers to a methyl (1 carbon atom), ethyl (2carbon atoms), propyl (3 carbon atoms) or butyl (4 carbon atoms) group.All possible isomers of the indicated alkyl are also included. Thus“propyl” includes isopropy, “butyl” includes n-butyl, isobutyl andtbutyl, etc.

[0122] As used herein, “amphiphilic” refers to a molecule that containsboth hydrophilic and lipophilic (or, synonymously, hydrophobic)moieties.

[0123] Hydrophilic means “water-loving.” The hydrophilic moiety of anamphiphilic molecule has an affinity for and is generally miscible withwater. If placed at a water/water-immiscible liquid (or a water/air)interface, the hydrophilic moiety will partition into the water layer.Examples of hydrophilic moieties include, without limitation, hydroxyl,methoxy, phenol, carboxylic acids and salts thereof, methyl and ethylesters of carboxylic acids, amides, amino, cyano, ammonium salts,sulfonium salts, phosphonium salts, polyethyleneglycols, epoxy groups,acrylates, sulfonamides, nitro, —OP(O)(OCH₂CH₂N⁺RR′R″)O⁻, guanidinium,aminate, acrylamide and pyridinium.

[0124] Lipophilic means “lipid-loving,” which, because lipids are oily,water insoluble compounds, is understood to mean generally “oil-loving.”The lipophilic moiety of an amphiphilic molecule avoids water and has anaffinity for and is generally miscible with water-immiscible liquids.Thus, if placed at a water/water immiscible liquid (or a water/air)interface, a lipophilic moiety will partition into the water-immisibleliquid layer (or into the air). The most common example of a lipophilicmoiety is a long, straight or branched chain hydrocarbon. Presentlypreferred lipophilic groups consist of at least eight (8) carbon atomsin a branched or straight chain. More preferably, the total number ofcarbon atoms in the chain will be 10 or more, still more preferably 12or more. A straight chain or each branch of a branched chain maycomprise any number of carbon atoms over the indicated minimum. However,the straight chain or each branch of a branched chain will comprise amaximum of 28 carbon atoms in a presently preferred embodiment of thisinvention. Each chain may independently comprise, without limitation,alkenyl, alkynyl, alicyclic or aromatic groups. Each chain may alsocontain, interspersed among the carbons of the chain, one or moresilicon atoms substituted with alkyl, alkenyl, alkynyl, alicyclic oraryl groups. Likewise the carbon atoms of each chain may independentlybe substituted with one or more fluorine atoms.

[0125] Other lipophilic and hydrophilic moieties useful in the presentinvention will become apparent to those skilled in the art based on thedisclosure herein. All such moieties are within the scope of thisinvention.

[0126] Based on the above, it should be clear that an amphiphilicmolecule, placed at a water/water-immiscible liquid (or water/air)interface will orient itself such that its hydrophilic moiety is in thewater layer and its lipophilic moiety is in the water-immiscible layer(or in the air).

[0127] In general, a “synthon” refers to a molecule that can beconnected with other molecules, which may be the same as, or differentthan, the initial molecule and each other, to create a larger molecule.As used herein, a “synthon” refers to a multifunctional organic moleculeof predominantly one stereochemical configuration. It may also refer toa molecule that is predominantly a single enantiomer. By“multifunctional” is meant that the molecule is substituted with atleast two functional groups, which may be the same as, or differentthan, each other. Connection of synthons of this invention to createlarger molecular entities occurs through covalent bonds resulting fromreaction of a functional group on one synthon with a functional group onanother synthon. A synthon may also be substituted with additionalfunctional groups that do not participate in synthon interconnectionsbut rather impart selected physical or chemical characteristics to thesynthon. Presently preferred synthons of this invention are cyclic.

[0128] By a “cyclic” synthon is meant a monocyclic or multicyclic ringsystem. The monocyclic ring or each ring of a multicyclic system mayindependently be aryl, heteroaryl, alicyclic or heteroalicyclic. “Aryl”refers to an all-carbon ring that contains a π-electron system that isdelocalized throughout the ring, that is, the ring is “aromatic.”“Heteroaryl” refers to an aromatic ring that contains nitrogen, oxygenor sulfur in addition to carbon. “Alicyclic” refers to an all-carbonring that, while it may contain one or more double bonds, does not havea fully delocalized π-electron system. “Heteroalicyclic” refers to aring that contains atoms other than carbon and that, likewise, does nothave a fully delocalized π-electron system. Multicyclic ring systems mayconsist of fused rings, i.e., each ring shares at least one ring atomwith another ring or they may simply be connected to one another throughone or more covalent bonds. Examples of cyclic synthons of thisinvention include, without limitation, benzene, naphthalene, anthracene,phenylene, phenathracene, pyrene, triphenylene, phenanthrene, pyridine,pyrimidine, pyridazine, biphenyl, bipyridyl, cyclohexane, cyclohexene,decalin, piperidine, pyrrolidine, tetrahydropyran, tetranhydrothiane,1,3-dioxane, 1,3-dithiane, 1,3-diazane, tetrahydrothiophene,tetrahydrofuran, pyrrole, cyclopentane, triptycene, adamantane,bicyclo[2.2.1]heptane, bicyclo[2.2.1]heptene, bicyclo[2.2.2]octane,bicyclo[2.2.2]octene, bicyclo[3.3.0]octane, bicyclo[3.3.0]octene,bicyclo[3.3.1]nonane, bicyclo[3.3.1]nonene, bicyclo[3.2.2]nonane,bicyclo[3.2.2]nonene, bicyclo[4.2.2]decane, 7-azabicyclo[2.2.1]heptane,1,3-diazabicyclo[2.2.1]heptane, spiro[4.4]nonane and the like.

[0129] As used herein, a “linker” refers to the reaction product of afunctional group on one synthon with a functional group on anothersynthon resulting in a bridge of covalently bonded atoms betweensynthons. The reaction may involve the direct chemical interaction of afunctional group on one synthon with a functional group on anothersynthon to form the linker. For example, a linker might comprise anester, which is the reaction product of a hydroxyl group on one synthonwith an acid or acid halide on another synthon. Another example is anamide, which would result from the reaction of an amine on one synthonwith an acid or acid halide on another synthon. A further example wouldbe the reaction of an aldehyde or ketone on one synthon with an amine onanother synthon to form an imine. A linker might comprise the reactionproduct of a 2+2 cycloaddition of two alkenes, one on each synthon. Alinker could also contain one or more atoms provided by a moiety otherthan the two functional groups. This external moiety is selected so asto react with the functional group on one synthon to form anintermediate that then reacts with a functional group on another synthonto form the covalent bridge of atoms between the synthons. An example,without limitation, of such a linker is the reaction product of an aminogroup on one synthon, a methyl ketone on another synthon andformaldehyde as the external molecule. Under either acidic or basicconditions, this combination of moieties will enter into the Mannichreaction. In presently preferred embodiments of this invention, thelinker is the reaction product of a functional group directly bonded toone synthon with a functional group directly bonded to another synthon.Thus, a presently preferred linker is the imine, —CH═N—, resulting fromthe reaction of an aldehyde, —CH═O, on one synthon with an amine, —NH₂,on another synthon. Other presently preferred linkers are esters andamides, which are discussed above. It is also possible, and is withinthe scope of this invention, that the linker may be separated from oneor both synthons by a spacer. The spacer can be any chemical entity thatforms a bridge of covalently bonded atoms between the synthon and afunctional group and that does not interfere with the linker-formingreaction. The simplest example of a spacer is methylene, —CH₂—; forexample, if a methylene spacer were inserted between an aldehyde groupand its synthon in the above imine linker-forming reaction, the linkerwould be —CH₂CH═N—. A list of presently preferred linker-formingfunctional groups and the linkers that they form are shown in Table 1.TABLE 1 Functional Group A Functional Group B Linker Formed 1 R—NH₂R′—C(O)H R—N═CH—R′ 2 R—NH₂ R′—CO₂R″ R—NHC(O)—R′ 3 R—OH R′—CO₂R″R—OC(O)—R′ 4 R—X R′—Ona R′—O—R 5 R—SH R′—SH R—S—S—R′ 6 R—X R′Sna R—S—R′7 R—X (R′)₂NH R—N—(R′)₂ 8 R—X (R′CH₂)CuLi R—CH₂—R′ 9 R—X R′—X R—R′ 10R—Sna R′C(O)OR″ R′C(O)SR 11 R—X

12

13 R—MgX R′C(O)H RCH(OH)R′ 14 R—NH₂

15 R—MgX

16

R′—X

17 RC(O)H R′C(O)H RHC═CHR′ 18

R′C(O)Cl

19 RN═C═O R′NH₂

20 RN═C═O HOR′

21 RC(O)H R′NH—NH₂ RCH═NNHR′ 22 R—OH R′OC(O)X ROC(O)OR′ 23

R′—SH

24

25

26

(CH₃)₂(R′)—SiH

27

28 RP(O)(OH)₃ R′OH RP(O)(OH)₂OR′

[0130] Other linkers and spacers will become apparent to those skilledin the art based on the disclosure herein; all such linkers and spacersare within the scope of this invention.

[0131] In general, a “module” refers to two or more synthons bonded toone another by linkers. In particular, an “amphiphilic module” refers toa module in which one or more of the synthons is substituted with one ormore lipophilic moieties and one or more of the synthons is substitutedwith one or more hydrophilic moieties. The same synthon may, if desired,be substituted with both a lipophilic and a hydrophilic moiety. Apresently preferred module comprises a two-dimensional array of three(3) or more synthons in which each synthon is covalently bonded to twoother synthons to form a ring of synthons. It is also a presentlypreferred embodiment of this invention that the ring of synthons, i.e.,the amphiphilic module, defines a pore.

[0132] As used herein, a “pore” refers to the hole created by the ringof synthons that form a module.

[0133] As used herein, a “nanopore” refers to a pore, which is from 0.5nanometer (nm) to approximately 100 nm in diameter.

[0134] As used herein, an “activated acid” refers to a —C(O)R moiety inwhich the R is readily displaced by a nucleophile to form a covalentbond between the —C(O)— and the nucleophile. Examples, withoutlimitation, of activated acids include acid chlorides, acid fluorides,p-nitrophenyl esters, pentafluorophenyl esters and N-hydroxysuccinimideesters.

[0135] As used herein, a “reagent” refers to a chemical entity or aphysical agent w that interacts with functional groups to cause orfacilitate the reaction of the functional groups to form a covalent bondor chain of covalent bonds between the moieties to which the functionalgroups are bonded. Examples of chemical reagents are, withoutlimitation, acids and bases. Examples of physical agents are, withoutlimitation, ultraviolet light, ion plasma and temperature changes. Inaddition to causing or facilitating the reaction of functional groups,the reagent might also itself react with one of the functional groups toform an intermediate chemical entity. The intermediate then reacts withanother functional group to create a chain of covalently bonded atomsbetween the moieties to which the functional groups are attached. An“intermediate” refers to a chemical entity that forms during a reactionbut which is not itself isolated, in fact is often not isolable, butwhich reacts further with other entities in the reaction mixture to givea final product.

[0136] As used herein, an “amino acid residue” refers to the chemicalentity formed when a compound comprising at least one amino (—NH₂) andat least one carboxyl (—C(O)O—) group reacts, through the amino orcarboxyl group, with an atom or functional group of a synthon. Whicheverof the two groups, is not participating in the linker or connectorforming reaction may be blocked with a removable protective group.

[0137] As used herein, “bond,” “bonding” or “bonded” refers, unlessotherwise expressly stated, to covalent bonds between the entities whichare the subject of the bonding.

[0138] As used herein, the phrase “confer selected chemical or physicalcharacteristics or combinations thereof on the module” refers tofunctional groups that are present on the modules for purposes otherthan forming linkers, forming connectors, or conferring amphiphilicityon the module. For example, without limitation, a functional group mightbe bonded to the module in such a manner that it extends into the poreof the module and is capable of chelating a particular atom or moleculeshould that atom or molecule attempt to traverse the pore. Thefunctional group might be a charged species, e.g., a carboxylate anionor ammonium group, which could be positioned in or near a pore to trapoppositely-charged species. A functional group that alters electricalconductivity in the region of a pore might be incorporated into amodule. The functional group might also be one that varies thehydrophilicity or lipophilicity in the vicinity of a pore. Of course, afunctional group might also be bonded to the module at locations otherthan the pore and might be used to modify other chemical or physicalcharacteristics of the module. A functional group might also serve morethan one purpose. For example, without limitation, a functional groupmight initially be part of a moiety that confers hydrophilicity on amodule. Once the module has formed a Langmuir film, the functional groupmight be used to form a connector.

[0139] As used herein, a “functional group” or “chemical moiety” refersbroadly to any group that is covalently bonded, directly or indirectly,to any of the synthons that comprise the module. By “indirectly” ismeant that the functional group can be separated form the synthon's ringstructure by one or more spacers. The terms include, but are not limitedto, the traditional groups considered “functional” by those skilled inthe art, e.g., amino (—NH₂), hydroxyl (—OH), cyano (—C≡N), nitro (NO₂),carboxyl (—COOH), formyl (—CHO), keto (—CH₂C(O)CH₂—), alkenyl (—C═C—),alkynyl (—C≡C—), halo (F, Cl, Br and I) groups and the like. The termalso refers to groups such as aryl, heteroaryl, alicyclic andheteroalicyclic, which may themselves be further substituted with one ormore of the preceding groups.

[0140] An amphiphilic module of the present invention is comprised ofthree or more synthons covalently bonded to one another to form a ring.In a presently preferred embodiment, the ring of synthons circumscribesan open region or pore. In a further presently preferred embodiment ofthis invention the pore is a nanopore. Thus, a first synthon iscovalently bonded to a second synthon through a linker, the secondsynthon is bonded to a third synthon through another linker, the thirdto a fourth through yet another linker and so on until the desirednumber of synthons have been linked. The last synthon in the chain isthen covalently bonded to the first synthon through a linker to form aring of synthons that encloses an open region, which comprises thenanopore. In a presently preferred embodiment of this invention, thesynthons are prepared or isolated as essentially single configurationalisomers or as essentially pure enantiomers. By “essentially” is meant asnear to configurational or enantiomeric purity as is practicallyachievable. In general, this means at least 80%, preferably 90% and mostpreferably 98+% pure.

[0141] Synthons

[0142] To avoid the need to separate single configurational orenantiomeric isomers from complex mixtures resulting from non-specificreactions, it is preferred to employ stereospecific, or at leaststereoselective, reactions in the preparation of the synthons of thisinvention. The following are examples of synthetic schemes that employsuch reactions to give several classes of synthons useful in thepreparation of amphiphilic modules of this invention. The examples arenot intended to be, and are not to be construed as, limiting on thescope of this invention in any manner whatsoever, it being understoodthat countless synthons and schemes for their preparation will becomeapparent to those skilled in the art based on the disclosures herein.All such synthons and schemes are within the scope of this invention.For clarity, no lipophilic moieties are shown on the structures in thefollowing examples. However, it is understood that any of the followingsynthetic schemes could readily be modified to include a step for theinclusion of a lipophilic moiety if in fact it were desired to have suchon the particular synthon.

[0143] 1,3-Diaminocyclohex-5-ene Synthons

[0144] An approach to this class synthons is outlined in Scheme 1. Thekey reaction in this process is the enzymatically assisted partialhydrolysis of the

[0145] symmetrical diester S1-1 (for the sake of clarity, compounds willbe numbered in relation to the scheme in which they appear; thus “S1-1”refers to the structure 1 in Scheme 1, etc.) to give enantiomericallypure S1-2. S1-2 was subjected to the Curtius reaction and then quenchedwith benzyl alcohol to give protected amino acid S1-3. Iodolactonizationof carboxylic acid S1-4 followed by dehydrohalogenation givesunsaturated lactone S1-6. Opening of the lactone ring with sodiummethoxide gives alcohol S1-7, which is converted with inversion ofconfiguration to S1-8 in a one-pot reaction involving mesylation, SN₂displacement with azide, reduction and protection of the resulting aminewith di-tert-butyl dicarbonate. Epimerization of S1-8 to the more stablediequatorial configuration followed by saponification gives carboxylicacid S1-10. S1-10 is subjected to the Curtius reaction. A mixedanhydride is prepared using ethyl chloroformate followed by reactionwith aqueous NaN₃ to give the acyl azide, which is thermally rearrangedto the isocyanate in refluxing benzene. The isocyanate is quenched with2-trimethylsilylethanol to give differentially protected tricarbamateS1-11. Reaction with trifluoroacetic acid (TFA) selectively deprotectsthe 1,3-diamino groups to provide the desired synthon S1-12.

[0146] Norbornane Diamine Synthons

[0147] Norbornanes (bicycloheptanes) are presently preferred synthons ofthis invention due, in part, to the relative ease with whichstereochemically controlled multifunctionalization can be achieved. Forexample, Diels-Alder cycloaddition can be used to form norbornanesincorporating various functional groups having specific, predictablestereochemistry. Enantiomerically enhanced products may also be obtainedthrough the use of appropriate reagents, thus limiting the need forchiral separations.

[0148] 1,2-Diaminonorbornane Synthons

[0149] An approach to a this class synthon is outlined in Scheme 2.5-(Benzyloxy-methyl)-1,3-cyclopentadiene (S2-13) was reacted with

[0150] diethylaluminum chloride Lewis acid complex of di-(l)-menthylfumarate (S2-14) at low temperature to give the diastereomerically purenorbornene S2-15. Saponification with potassium hydroxide in aqueousethanol gives the diacid S2-16, which is subjected to a tandem Curtiusreaction with diphenylphosphoryl azide (DPPA), the reaction productbeing quenched with 2-trimethylsilylethanol to give the biscarbamateS2-17. Deprotection with TFA gives diamine S2-18.

[0151] Another approach to this synthon class is outlined in Scheme 3.Opening of anhydride S3-19 with methanol in the presence of quinidinegives the enantiomerically pure ester acid S3-20. Epimerization of theester group with sodium methoxide (NaOMe) gives S3-21. A Curtiusreaction with DPPA followed by quenching with trimethylsilylethanol givecarbamate S3-22. Saponification with NaOH gives the acid S3-23, whichthen undergoes a Curtius reaction,

[0152] which is quenched with benzyl alcohol to give differentiallyprotected biscarbamate S3-24. Compound S3-24 can be fully deprotected toprovide the diamine or either of the carbamates can be selectivelydeprotected.

[0153] endo,endo-1,3-Diaminonorbornane Synthons

[0154] An approach to this class synthons is outlined in Scheme 4.5-Trimethylsilyl-1,3-cyclopentadiene (S4-25) is reacted with thediethylaluminum chloride Lewis acid complex of di-(l)-menthyl fumarateat low temperature to give nearly diastereomerically pure norborneneS4-26. Crystallization of S4-26 from alcohol results in recovery ofgreater than 99% of the single diastereomer. Bromolactonization followedby silver mediated rearrangement gives mixed diester S4-28 with analcohol moiety at the 7-position. Protection of the alcohol with benzylbromide and selective deprotection of the methyl ester gives the freecarboxylic acid S4-30. A Curtius reaction results in trimethylsilylethylcarbamate norbornene S4-31. Biscarbonylation of the olefin in methanol,followed by a single-step deprotection and dehydration gives themonoanhydride S4-33. Quinidine mediated opening of the anhydride withmethanol gives S4-34. Curtius transformation of S4-34 gives thebiscarbamate S4-35, which is deprotected with TFA or tetrabutylammoniumfluoride (TBAF) to give diamine S4-36.

[0155] Another approach to this class of synthons is outlined in Scheme5. Benzyl alcohol opening of S3-19 in the presence of quinidine givesS5-37 in high enantiomeric excess. Iodolactonization followed by NaBH₄reduction gives lactone S5-39. Treatment with NaOMe liberates the methylester and the free alcohol to generate S5-40. Transformation of thealcohol S5-40 to the inverted t-butyl carbamate protected amine S5-41 isaccomplished in a one-pot reaction by azide deplacement of the mesylateS5-40 followed by reduction to the amine, which is protected withdi-tert-butyl dicarbonate. Hydrogenolytic cleavage of the benzyl esterand epimerization of the methyl ester to the exo configuration isfollowed by protection of the free acid with benzyl bromide to giveS5-44. Saponification of the methyl ester followed by atrimethylsilylethanol quenched Curtius reaction

[0156] gives the biscarbamate S5-46, which is cleaved with TFA to givethe desired diamine S5-47.

[0157] exo,endo-1,3-Diaminonorbornane Synthons

[0158] An approach to this class of synthons is outlined in Scheme 6.p-Methoxybenzyl alcohol opening of norbornene anhydride S3-19 in thepresence of quinidine gives monoester S6-48 in high enantiomeric excess.Curtius reaction of the free acid gives protected all endomonoacid-monoamine S6-49. Biscarbonylation and anhydride formation givesexo-monoanhydride S6-51. Selective methanolysis in the presence ofquinine gives S6-52. A trimethylsilylethanol quenched Curtius reactiongives biscarbamate S6-53. Epimerization of the two esters results in themore sterically stable S6-54. Cleavage of the carbamate groups providessynthon S6-55.

[0159] Amphiphilic Modules

[0160] Once the desired synthons are in hand, the next step is toconnect them to one another through linkers to form the amphiphilicmodules of this invention. This can be accomplished in a concerted orstepwise fashion.

[0161] A concerted module synthesis requires two synthons, each of whichis substituted with at least two functional groups. The groups areselected such that a functional group “A” bonded to one of the synthonscan react only with one functional group, “A*” on the other synthon.Likewise, the other functional group, “B,” on the first synthon canreact only with “B*” on the other synthon. When the synthons arecombined under appropriate conditions, a chain of alternating synthonswill form until an “A” (or “B”) on the last synthon to be added to thechain encounters an “A*” (or “B*”) on the first synthon, which willresult in the creation of a ring of synthons, i.e., a module. Scheme 7illustrates a concerted module synthesis.

[0162] 1,2-Diaminocyclohexane, S7-1, is a synthon in which A and B arethe same, i.e., amino groups. Likewise,2,6-diformyl-4-dodec-1-ynylphenol, S7-2, is a synthon in which A* and B*are the same, i.e., formyl groups. Under the proper conditions, A and Bwill react with A* and B* to form imine linkers. The hexamer is theproduct shown below; it is in fact the thermodynamic product. However,the tetramer and octamer may also be formed depending on the reactionsconditions. In fact, by appropriate choice of reaction conditionsincluding, without limitation, synthon concentrations, solvent, reactiontemperature and reaction time enhanced yields of various sized rings canbe realized.

[0163] The imine groups of S7-3 can be reduced, e.g. with sodiumborohydride, to give amine linkers. If the reaction is carried out using2,6-di(chlorocarbonyl)-4-dodec-1-ynylphenol instead of2,6-diformyl-4-dodec-1-ynylphenol, the resulting module will containamide linkers. Similarly, if 1,2-dihydroxycyclohexane is reacted with2,6-di(chlorocarbonyl)-4-dodec-1-ynylphenol, the resulting module willcontain ester linkers. Many such concerted module syntheses will becomeapparent to those skilled in the art based on the disclosures herein;all such syntheses are within the scope of this invention.

[0164] The stepwise synthesis of modules is somewhat more versatile. Afirst synthon is substituted with one protected and one unprotectedfunctional group. By “protected” is meant that a functional group issubstituted with a readily removable entity that, while bonded to thefunctional group, prevents the group from entering into the reactions itnormally would.

[0165] A second synthon is provided that is substituted with anunprotected functional group that will react under appropriateconditions with the unprotected functional group on the first synthon togive a dimer. The second synthon is also substituted with anotherfunctional group that is either protected or that will not react underthe dimer-forming conditions. The dimer, which may be isolated andpurified or used directly in the next step, is then contacted with athird synthon, which also carries two functional groups, only one ofwhich is capable or reacting with the remaining functional group of thesecond synthon. This forms a trimer. The trimer is reacted with a fourthsynthon to form a tetramer and so on until the desired number ofsynthons has been added to the chain. A last synthon to be added to thechain is substituted with a functional group that is capable of reactingonly with the second functional group, after it is deprotected, of thefirst synthon. A ring of synthons, that is, a module of this invention,will thus be formed. The stepwise synthesis is more time consuming anddifficult to perform but the choice of synthons is virtually limitlessand permits much greater diversity in the structure of the amphiphilicmodules. Scheme 8 illustrates a step-wise synthesis of module SC8-1.

[0166] Compound S8-2 is reacted with SC8-3, in which the phenol isprotected as the benzyl ether and the nitrogen is shown as protectedwith a group “P,” which can be any of a large number of protectinggroups well-known in the art, in the presence of methanesulfonylchloride (Endo, K.; Takahashi, H. Heterocycles, 1999, 51, 337), to giveS8-4. Removal of the N-protecting group give the free amine S8-5, whichcan be coupled with synthon S8-6 using any standard peptide couplingreaction such as BOP/HOBt to give S8-7. Deprotection/coupling isrepeated, alternating synthons S8-3 and S8-6 until a linear constructwith eight residues is obtained. The remaining acid and amine protectinggroups on the 8-mer are removed and the oligomer is cyclized usingstandard procedures (e.g., Caba, J. M., et al., J. Org. Chem., 2001,66:7568 (PyAOP cyclization) and Tarver, J. E. et al., J. Org. Chem.,2001, 66:7575 (active ester cyclization). The R group may be anyfunctional group that is desired in the target module or it can be alink to a solid support such as a Wang resin. Using such a solid supportmight simplify the procedure by obviating purification of intermediatesalong the way. It is even be possible to do the final cyclization in asolid phase mode. In fact, a “safety-catch linker” approach (Bourne, G.T., et al., J. Org. Chem., 2001, 66:7706) might be used to obtaincyclization and resin cleavage in a single operation.

[0167] Module Pores

[0168] In a presently preferred embodiment of this invention, the ringof synthons; i.e., the module, defines a cavity or pore in the module.As noted previously, in a presently preferred embodiment of thisinvention the pore is a nanopore. The size of the pore will determinethe size of molecules that can pass through the module. Of course, sizeneed not be the sole determinant of what will be able to pass through apore. Ionic, chelating or coordinating moieties, moieties that renderthe interior of the pore more or less hydrophilic, etc., can be disposedwithin or proximate to a pore to provide an additional means of controlover the nature of molecules that will pass through. Moieties can beplaced within pores as part of the synthons initially or they can beadded later by various derivatization reactions. For example, moduleS7-1 could be reacted with ClC(O)(CH₂)₂C(O)OCH₂CH₃ to convert the phenolgroups to succinyl esters.

[0169] The size of a pore will depend on the nature of the synthonsused, the number of synthons in a module and the nature of the linkers.A first approximation to pore size can be obtained using quantummechanical (QM) and molecular mechanical (MM) computations.

[0170] As the basis for the computations, modules were assumed toconstitute two synthons, “A” and “B,” and all linkers were assumed to bethe same. As it turns out, the modules approximate various regularpolyhedrons quite well depending on the number of synthons in themodule. Thus, when stereochemically defined modules comprised of 4, 6,and 8 synthons were subjected to MM3 energy minimization, the structuresshown in FIGS. 1A-C, which are at, or very near, the thermodynamicenergy minimums were obtained. As can be seen, the tetramer essentiallydescribes a parallelogram, the hexamer an equilateral triangle and theoctamer a rhombus. For the purposes of QM and MM computations, root meansquare deviations in the pore areas were computed over the dynamic runs.

[0171] For quantum mechanical computations, each module was firstoptimized using the MM+force field approach of Allinger (JACS, 1977,99:8127) and Burkert, et al., (Molecular Mechanics, ACS Monograph 177,1982). They were then re-optimized using the AM1 Hamiltonian (Dewar, etal., JACS, 1985, 107:3903; Dewar, et al., JACS, 1986, 108:8075; Stewart,J. Comp. Aided Mol. Design, 1990, 4:1). To verify the nature of thepotential energy surface in the vicinity of the optimized structures,the associated Hessian matrices were computed using numerical doubledifferencing.

[0172] As for MM computations, the OPLS-AA force field approach(Jorgensen, et al., JACS, 1996, 118:11225) was used. For imine linkers,the dihedral angle was confined to 180°±10°. The structures wereminimized and equilibrated for one picosecond using 0.5 femtosecond timesteps. Then a 5 nanosecond dynamics run was carried out with a 1.5femtosecond time step. Structures were saved every picosecond. Theresults are shown in Tables 2 and 3.

[0173] In Table 2, Synthon “A” is 2,6-benzenediol while in Table 3,synthon “A” is 2,7-naphthanediol. Synthon B is shown in the left-handcolumn. Nanopore sizes derived from QM and MM computations for variouslinkers and module size are shown. TABLE 2 TETRAMER TETRAMER HEXAMERHEXAMER OCTAMER OCTAMER SYNTHON B QM MM QM MM QM MM trans-1,2- imine(trans) Imine (trans) cyclohexane 14.3 Å² 13.2 ± 1.4 Å² trans-1,2-Acetylene cyclohexane 14.3 Å² trans-1,2- Amine Amine cyclohexane 23.1 Å²13.9 ± 1.9 Å² trans-1,2- Amide Amide cyclohexane 19.7 Å² 17.5 ± 2.0 Å²trans-1,2- Ester Ester cyclohexane 18.9 Å² 19.6 ± 2.0 Å² Equatorial-1,3-imine (trans) Imine (trans) imine (trans) Imine (trans) cyclohexane 18.1Å² 21.8 ± 1.6 Å² 66.2 Å² 74.5 ± 7.7 Å² Equatorial-1,3- Amine Aminecyclohexane 14.7 Å² 19.9 ± 2.6 Å² Equatorial-1,3- Amide Amidecyclohexane 24.8 Å² 21.7 ± 1.8 Å² Equatorial-1,3- Ester Estercyclohexane 22.9 Å² 22.8 ± 2.4 Å² Equatorial-3- imine (trans) imine(trans) imine (trans) Imine (trans) imine (trans) Imine (trans) mino-oxygen-xygen oxygen-oxygen 18.4 Å² 21.0 ± 1.5 Å² 56.7 Å² 60.5 ± 8.3 Å²cyclohexene distance distance 2.481 Å 3.7 ± .3 Å trans-1,2- imine(trans) Imine (trans) pyrrolidine 10.4 Å² 9.2 ± 1.4 Å² Equatorial-1,3-imine (trans) Imine (trans) piperidene 19.2 Å² 20.9 ± 1.1 Å²Endo-exo-1,2- imine (trans) Imine (trans) bicycloheptane 11.1 Å² 14.1 ±+11 Å² Endo-endo-1,3 imine (trans) Imine (trans) bicycloheptane 18.8 Å²20.7 ± 1.4 Å² Endo-exo-1,3- Imine Imine bicycloheptane 19.5 Å² 10.1 ±+4.9 Å² Equatorial-1,3- Amine Amine cyclohexane 9.8 Å² 9.9 ± 2.4 Å²Endo-endo-1,3- imine (trans) Imine (trans) bicyclooctene 18.9 Å² 21.6 ±1.5 Å² Endo-exo-1 3- imine (trans) Imine (trans) bicyclooctene 15.6 Å²18.7 ± 1.6 Å² Equatorial-3,9- Imine (trans) Imine (trans) decalin 35.4Å² 40.0 ± 2.2 Å²

[0174] TABLE 3 HEXAMER HEXAMER SYNTHON B QM MM Trans-1,2- imine (trans)imine (trans) cyclohexane 23.5 Å² 25.4 ± 4.9 Å² Endo-endo-1,3- imine(trans) imine (trans) bicycloheptane 30.1 Å² 30.0 ± 3.6 Å²

[0175] The computed nanopore size was tested and confirmedexperimentally using a voltage-clamped bilayer procedure. Modules areinserted into a lipid bilayer, for example, the bilayer formed byphosphatidylcholine and phosphatidylethanolamine. On one side of thebilayer is placed a solution containing a test cationic species. On theother side is a solution containing an cationic species known to be ableto pass through a pore of the calculated size. Anions required forcharge neutrality are selected such that they will not pass throughpores of the calculated size. When a positive potential is created inthe solution on the side of the lipid bilayer containing the testspecies, if the test cations are of such a size that they cannot passthrough the pores in the modules, no current will be detected. Thevoltage is then reversed to create a positive potential on the side ofthe lipid bilayer having the solution containing the cationic speciesknown to be able to traverse the pore. Observation of the expectedcurrent confirms the integrity of the membrane and the availability ofthe pores as transporters of cations of that size (and, of course,smaller) across the membrane.

[0176] Using the above technique, a hexameric module comprised ofR,R-1,2-transdiaminohexane and 2,6-diformal-4-(1-dodec-1-ynyl)phenol asthe synthons and imine groups as the linkers (the first module in Table2) was inserted in the abovedescribed lipid bylayer. A number ofdifferent ionic species were then tested to see if they could traversethe pore. The results are shown in Table 4. TABLE 4 Calculated van derWaals Calculated van radius of ionic der Waals radius Does ionic species(VdW) of ionic species species pass (in Angstroms, with one waterthrough Ionic species Å) shell nanopore? Na⁺ 1.0 2.2 Yes K⁺ 1.3 2.7 YesCa²⁺ 1.0 2.7 Yes Mg²⁺ 0.7 2.8 Yes NH₄ ⁺ 1.9 2.9 Yes Cs⁺ 1.7 3.0 YesMeNH₃ ⁺ 2.0 3.0 Yes EtNH₃ ⁺ 2.6 3.6 No NMe₄ ⁺ 2.6 3.6 NoAminoguanidinium 3.1 4.1 No NEt₄ ⁺ 3.9 4.4 No Choline 3.8 4.8 NoGlucosamine 4.2 5.2 No

[0177] From Table 4 it can be deduced that the cut-off for passagethrough the pore in the selected module is a van der Waals radius ofsomewhere between 2.0 and 2.6 A. In Table 2, the QM and MM computednanopore sizes are given as areas. Using the equation for area of acircle, A=πr², the computed area of the pore in the first module ofTable 1, 14.3 Å², gives a value for r of 2.13 Å. Thus, ions having vander Waals radii of less than 2.13 would be expected to traverse the poreand those with larger radii would not. This is exactly what wasobserved. CH₃NH₃ ⁺, having a radius of 2.0 Å, passed through the porewhile CH₃CH₂NH₃ ⁺, with a radius of 2.6 Å, did not. Without being heldto a particular theory, the observed ability of hydrated ions to passthrough the pore may be due to partial dehydration of the species at thepore with water molecules and ions passing through single file and thenre-coordinating on the other side. In addition, the ions may coordinatewith atoms of the pore during the process.

[0178] Arrays of Modules

[0179] Modules of the present invention can be arranged in a virtuallyinfinite number of ways. They can be randomly distributed in a planedefined by the plane of the ring of synthons without any means ofcontrolling the location of individual modules. The randomly distributedmodules may be connected to one another to form a somewhat more robustarray. On the other hand, the modules may be arranged in an orderedarray such as, without limitation, a close-packed or a dendridic array.In a presently preferred embodiment of this invention, a two-dimensionalclose-packed planar array of modules is constructed.

[0180] Two-Dimensional Close-Packed Planar Arrays

[0181] It is, of course, understood that the arrays cannot technicallybe two-dimensional because atoms have volume. Furthermore, functionalgroups attached to the modules may extend above and below the planedefined by the rings of synthons that comprise the modules that, inturn, comprise the arrays. Thus, as used herein, “two-dimensional”refers simply to the fact that presently preferred arrays of thisinvention are one module thick.

[0182] By “planar” is meant that the modules are disposed in a planedefined by the planes of the synthons comprising the modules.

[0183] As used herein, “close-packed” refers to an array in which, for agiven polygonal-shaped module, the edges of the polygon fit togethersuch that voids between the modules are minimized. For example, FIG. 2shows a two-dimensional planar close-packed array of hexameric (i.e.,essentially triangular) modules. In FIG. 2, the circles representsynthons. In FIG. 2A, the modules are shown in a close-packed arraywithout any means of maintaining the structure. Such arrays can beformed and may have practical application. However, in most instances,to form a robust array that can withstand a variety of external forcesand therefore should be more practically useful, it is preferred toconnect the modules to one another. This is depicted schematically inFIGS. 2B and 2C, in which the lines between the synthons representconnectors. A “connector,” as used herein, is similar to a linker inthat it is the reaction product of a functional group associated withone module with a functional group associated with a second module. Theterm “associated” is used to signify that a connector functional groupmay be separated from the synthon to which it is attached by asubstantially longer spacer than those used with linkers. That is,whereas functional groups comprising linkers are either bonded directlyto synthons or, at most, are separated by a methylene or two, connectorfunctional groups may be substantially remote from the synthon. Forexample, an acrylate double bond at the end of an 8C hydrophilic groupmay serve as a connector-forming functional group (see infra).

[0184] Connectors may be formed using one or more functional group oneach module. In FIG. 2B, one line is shown between adjacent modulesindicating a single connector formed by the reaction of one functionalgroup on each module. However, it is possible to have more than oneconnector between the same two modules, as shown in FIG. 2C, wherein twofunctional groups on each module have reacted to from connectors.

[0185] The connector functional groups may be bonded to a synthon alongan edge of a module (FIG. 2B) or at an apex (triangle/hexamer, FIG. 2C)or at a corner (tetramer, octamer). Of course, any combination of thesemay also be employed.

[0186] To bring the modules into close proximity such that connectorsmay be formed, their amphiphilicity is exploited. It is known in the artthat, when placed at the interface of water and a water-immisible liquid(or air), amphiphilic molecules will orient themselves such that theirhydrophilic moieties are immersed in the water layer and theirlipophilic moieties are in the water-immisible liquid layer (or extendup into the air). If pressure is applied horizontally to themonomolecular film of amphiphilic modules so formed, the modules willcondense into a close-packed array, called a Langmuir film. Theapparatus in which Langmuir films are created is called aLangmuir-Blodgett (L-B) trough. Langmuir films and L-B troughs are wellknown in the art. The following is an example of a procedure that can beemployed to form a Langmuir film. It is not to be construed as limitingthe scope of this invention in any way. The procedure is schematicallydepicted in FIG. 6.

[0187] Amphiphilic modules 4 are dissolved in HPLC-grade chloroform at aconcentration of approximately 1 mg/ml. The chloroform solution 3 isapplied to a water (Millipore Milli-Q) surface 2 in an L-B trough 1(such as that marketed by KSV, Helsinki, Finland). The chloroform isallowed to evaporate, leaving the amphiphilic modules on the surface ofthe water with their hydrophilic groups 5 immersed in the water andtheir lipophilic groups 6 in the air. The temperature in the system iscarefully controlled (preferably to within ±0.2° C. or better). Thebarriers 10 of the L-B trough are slowly compressed (1-10 mm/min). Thesurface pressure is monitored using an appropriate technique such as theWilhelmy plate procedure until a sudden change in surface pressuresignifies that the film has collapsed. Pressure is released until thefilm reforms. A plot of surface pressure as a function of the area ofwater surface available to each module at a constant temperature, knownas the surface pressure/area isotherm, often abbreviated “isotherm,” isan indicator of the monolayer properties of a material, which canconfirm that a Langmuir film has in fact formed. An example of anisotherm is shown for an amphiphilic synthon and an amphiphilic moduleof this invention in FIG. 3. The shape of the isotherm confirms that themodule does in fact form a Langmuir film on the surface of the water.Furthermore, it can be seen that the calculated water surface arearequired by the synthon and module when in a Langmuir film configurationagrees very well with that experimentally determined. The result of thecompression of the trough is the formation of a close-packed array 8 ofamphiphilic modules.

[0188] Once a Langmuir film has formed, selected functional groups will,by virtue of their pre-determined locations on the modules and thepredictable alignment of the amphiphilic modules in the Langmuir film,be located in the correct relationship to one another to react and formconnectors 9. As noted previously, the connector-forming functionalgroups may have served other purposes prior to being recruited forconnector duty. For example, a functional group might be employed aspart of a hydrophilic moiety to assist in the formation of a Langmuirfilm and then, once the film has formed, may be used to form aconnector. Other multiple-use functional groups will be envisioned bythose skilled in the art based on the disclosures herein and are withinthe scope of this invention.

[0189] A connector functional group may, as was the case with linkerprecursors, be covalently bonded directly to a synthon. In fact, thesame functional groups shown to form linkers in Table 1 may be used toform connectors in exactly the same way. In practice, if the samefunctional groups are going to be used for form both linkers andconnectors, those that will be used later to form connectors are blockedwith protecting groups that prevent their reaction until the protectinggroup is removed. As with linkers, connector formation may also comprisethe reaction of three or more moieties, for example, a functional groupon one module, a second functional group on an adjacent module and athird external molecule. An example of this would be the Mannichreaction, discussed above with regard to linkers.

[0190] However, an even broader range of external molecules may beuseful in the formation of connectors than in the formation of linkers.Some of these external molecules are shown in FIG. 4. In the figure, themodules are again shown as triangles, implying hexamers. Likewise, thecircles represent synthons and the solid lines, covalent bonds. It isunderstood, however, that the same functional groups could be used andthe same connector-forming reactions carried out with any size module.

[0191] Thus, bisamidates (FIG. 4A), dicarbonyidiimidazoles (FIG. 4B),bisboronic acids or esters (FIG. 4C) and acrylates (FIG. 4D) may be usedto form connectors. Numerous other connector-forming functional groups,reactants and reactions will become apparent to those skilled in the artbased on the disclosures herein and are within the scope of thisinvention.

[0192] It is presently preferred, however, that the distance betweenmodules as defined by the length of the connectors be such that theholes created between modules in the array by the connectors be smallerin size than the pores within the individual modules.

[0193] Two functional groups used to form two connectors may be bondedto the same synthon. Such an arrangement is depicted in FIG. 5. In FIG.5A, two amino groups are bonded to the same synthon in each module.Reaction with formaldeyde gives the connectors shown, i.e., aminals. InFIG. 5B, two mercapto (-SH) groups are shown bonded to the same synthon.These can be oxidatively coupled to form sulfides. It is, of course,possible, if desired, to have the amino or mercapto groups on differentsynthons and still form connectors. In FIG. 5C acrylate groups are showncoupled by a 2+2 cycloaddition reaction to form cyclobutane connectors.

[0194] As indicated above, connector-forming functional groups may beseparated from the modules by spacers just as linkers could be. However,connector functional groups may be separated from the ring of the moduleby a substantially greater distance than linkers, which usually, but notnecessarily, equates to a larger number of spacer groups, particularlyif the spacers are small moieties such as methylene (—CH₂—) groups. Forexample, in FIG. 5D, acrylate groups, which are separated from the bodyof the module by 7 methylene groups, may have initially been used ashydrophilic groups for the formation of a Langmuir film, are reactedwith added acrylate to form a polyacrylate connector.

[0195] Numerous other functional groups and reactions that could be usedto form connectors will become apparent to those skilled in the artbased on the disclosures herein and are within the scope of thisinvention.

[0196] A two-dimensional, close-packed planar array of modules bonded toone another by connectors to form a cohesive one module thick sheet isreferred to herein as a nanomembrane.

[0197] Applications

[0198] The modules of the present invention each contain a pore. In apresently preferred embodiment of this invention, the pores arenanopores, that is, they have a diameter between 0.5 and approximately100 nm. The simplest application would be one involving size exclusionseparations. By appropriate selection of synthons, number of synthons ineach module and linkers, pores, and more specifically nanopores, ofvirtually any size can be created. Such filters would be useful in suchapplications as ion separation, gas separation, small moleculeseparation, water purification, sewage treatment, toxin removal, etc.Physiological uses such as filtration of bacteria, fungi, viruses andthe like are also envisioned.

[0199] As mentioned previously, it is also possible to decorate theinterior of the pores of the modules of this invention with functionalgroups that alter the environment in and around the pores. Thus,separations based on factors other than size alone will be possibleusing the nanomembrane filters of this invention. Chelating groups, iontraps, hydrophilicity or lipophilicity affecting groups, antibodies andhistochemically active groups are but a few of the moieties that couldbe positioned proximate to or within the pores of the modules to affectthe nature of atoms/molecules/biological entities that can pass throughthe nanomembrane. Other modifications and uses of membranes of thisinvention will become apparent based on the disclosures herein and arewithin the scope of this invention.

EXAMPLES

[0200] Reagents were obtained from Aldrich Chemical Company and VWRScientific Products. All reactions were carried out under nitrogen orargon atmosphere unless otherwise noted. Solvent extracts of aqueoussolutions were dried over anhydrous Na₂SO₄. Solutions were concentratedunder reduced pressure using a rotary evaporator. Thin layerchromatography (TLC) was done on analtech Silica gel GF (0.25 mm) platesor on Machery-Nagel Alugram Sil G/UV (0.20 mm) plates. Chromatogramswere visualized with either UV light, phosphomolybdic acid, or KMnO₄.All compounds reported were homogenous by TLC unless otherwise noted.HPLC analyses were performed on a Hewlett Packard 1100 system using areverse phase C-18 silica column. Enantiomeric excess was determined byHPLC using a reverse phase (l)-leucine silica column from RegisTechnologies. All ¹[H] and ¹³[C] NMR spectra were collected at 400 MHzon a Varian Mercury system. Electrospray mass spectra were obtained bySynpep Corp., or on a Thermoquest Finnegan LC-MS system.

[0201] 2,6-Diformyl-4-bromophenol

[0202] Hexamethylenetetramine (73.84 g, 526 mmol) was added to TFA (240mL) with stirring. 4-Bromophenol (22.74 g, 131 mmol) was added in oneportion and the solution heated in an oilbath to 120° C. and stirredunder argon for 48 h. The reaction mixture was then cooled to ambienttemperature. Water (160 mL) and 50% aqueous H₂SO₄ (80 mL) were added andthe solution stirred for an additional 2 h. The reaction mixture waspoured into water (1600 mL) and the resulting precipitate collected on aBuchner funnel. The precipitate was dissolved in ethyl acetate (EtOAc)and the solution was dried over MgSO₄. The solution was filtered and thesolvent removed on a rotary evaporator. Purification by columnchromatography on silica gel (400 g) using a gradient of 15-40% ethylacetate in hexanes resulted in a isolation of the product as a yellowsolid (18.0 g, 60%).

[0203]¹H NMR (400 MHz, CDCl₃) δ 11.54 (s, 1H, OH), 10.19 (s, 2H, CHO),8.08 (s, 2H, ArH).

[0204] 2,6-Diformyl-4-(dodecyn-1-yl)phenol

[0205] 2,6-Diformyl-4-bromophenol (2.50 g, 10.9 mmol), 1-dodecyne (2.00g, 12.0 mmol), Cul (65 mg, 0.33 mmol), andbis(triphenylphosphine)palladium)II) dichloride were suspended indegassed acetonitrile (MeCN) (5 mL) and degassed benzene (1 mL). Theyellow suspension was sparged with argon for 30 min and degassed Et₃N (1mL) was added. The resulting brown suspension was sealed in a pressurevial, warmed to 80° C. and held there for 12 h. The mixture was thenpartitioned between EtOAc and KHSO₄ solution. The organic layer wasseparated, washed with brine, dried (MgSO₄) and concentrated underreduced pressure. The dark yellow oil was purified by columnchromatography on silica gel (25% Et₂O in hexanes) to give 1.56 g (46%)of the title compound.

[0206]¹H NMR (400 MHz, CDCl₃) 611.64 (s, 1H, OH), 10.19 (s, 2H, CHO),7.97 (s, 2H, ArH), 2.39 (t, 2H, J=7.2 Hz, propargylic), 1.59 (m, 3H,aliphatic), 1.43, (m, 2H, aliphatic), 1.28 (m, 11H, aliphatic), 0.88 (t,3H, J=7.0 Hz, CH₃).

[0207]¹³C NMR (400 MHz, CDCl₃) δ 192.5, 162.4, 140.3, 122.8, 116.7,91.4, 77.5, 31.9, 29.6, 29.5, 29.3, 29.1, 28.9, 28.5, 22.7, 19.2, 14.1.

[0208] MS (FAB): Calcd. for C₂₀H₂₇O₃ 315.1960; found 315.1958 [M+H]⁺.

[0209] 2,6-Diformyl-4-(dodecen-1-yl)phenol

[0210] 2,6-Diformyl-4-bromophenol (1.00 g, 4.37 mmol), 1-dodecene (4.8mL, 21.7 mmol), 1.40 g tetrabutylammonium bromide (4.34 mmol), 0.50 gNaHCO₃ (5.95 mmol), 1.00 g LiCl (23.6 mmol) and 0.100 g palladiumdiacetate (Pd(OAc)₂) (0.45 mmol) were combined in 30 mL degassedanhydrous dimethylformamide (DMF). The mixture was sparged with argonfor 10 min and then sealed in a pressure vial which was warmed to 82° C.and held for 40 h. The crude reaction mixture was partitioned betweenCH₂Cl₂ and 0.1 M HCl solution. The organic layer was washed with 0.1 MHCl (2×), brine (2×), and saturated aqueous NaHCO₃ (2×), dried overMgSO₄ and concentrated under reduced pressure. The dark yellow oil waspurified by column chromatography on silica gel (25% hexanes in Et₂O) togive 0.700 g (51%) of the title compound as primarily the Z isomer.

[0211]¹H NMR (400 MHz, CDCl₃) δ11.50 (s, 1H, OH), 10.21 (s, 2H, CHO),7.95 (s, 2H, ArH), 6.38 (d, 1H, vinyl), 6.25 (m, 1H, vinyl), 2.21 (m,2H, allylic), 1.30-1.61 (m, 16H, aliphatic), 0.95 (t, 3H, J=7.0 Hz,CH₃).

[0212] MS (FAB): Calcd. for C₂₀H₂₇O₃ 315.20; found 315.35 [M−H]⁻.

[0213] (1 R,6S)-6-Methoxycarbonyl-3-cyclohexene-1-carboxylic Acid (S1-2)

[0214] S1-1 (15.0 g, 75.7 mmol) was suspended in pH 7 phosphate buffer(950 mL). Pig liver esterase (2909 units) was added, and the mixturestirred at ambient temperature for 72 h with the pH maintained at 7 byaddition of 2M NaOH. The reaction mixture was washed with ethyl acetate(200 mL), acidified to pH 2 with 2M HCl, and extracted with ethylacetate (3×200 mL). The extracts were combined, dried, and evaporated toafford 13.8 g (99%) of S1-2.

[0215]¹H NMR: (CDCl₃) δ 2.32 (dt, 2H, 2_(ax)- and 5_(ax)-H's), 2.55 (dt,2H, 2_(eq)- and 5_(eq)-H's), 3.00 (m, 2H, 1- and 6-H's), 3.62 (s, 3H,CO₂Me), 5.61 (m, 2H, 3- and 4-H's).

[0216] Methyl (1 S,6R)-6-Benzyloxycarbonylaminocyclohex-3-enecarboxylate (S1-3)

[0217] S1-2 (10.0 g, 54.3 mmol) was dissolved in benzene (100 mL) underN₂. Triethylamine (13.2 g, 18.2 mL, 130.3 mmol) was added followed byDPPA (14.9 g, 11.7 mL, 54.3 mmol). The solution was refluxed for 20 h.Benzyl alcohol (5.9 g, 5.6 mL, 54.3 mmol) was added and reflux continuedfor 20 h. The solution was diluted with EtOAc (200 mL), washed withsaturated aqueous NaHCO₃ (2×50 mL), water (20 mL), and saturated aqueousNaCl (20 mL), dried and evaporated to give 13.7 g (87%) of S1-3.

[0218]¹H NMR: (CDCl₃) δ 2.19 (dt, 1H, 5_(ax)-H), 2.37 (tt, 2H, 2_(ax)-and 5_(eq)-H's), 2.54 (dt, 1H, 2_(eq)-H), 2.82 (m, 1H, 1-H), 3.65 (s,3H, CO₂Me), 4.28 (m, 1H, 6-H), 5.08 (dd, 2H, CH₂Ar), 5.42 (d, 1H, NH),5.62 (ddt, 2H, 3- and 4-H's), 7.35 (m, 5H, Ar H's).

[0219] (1 S, 6R)-6-Benzyloxycarbonylaminocyclohex-3-enecarboxylic Acid(S1-4)

[0220] S1-3 (23.5 g, 81.3 mmol) was dissolved in MeOH (150 mL) and thesolution cooled to 0° C. 2M NaOH (204 mL, 0.41 mol) was added, themixture allowed to come to ambient temperature and then it was stirredfor 48 h. The reaction mixture was diluted with water (300 mL),acidified with 2M HCl, and extracted with dichloromethane (250 mL),dried, and evaporated. The residue was recrystallized from diethyl etherto give 21.7 (97%) of S1-4.

[0221]¹H NMR: (CDCl₃) δ 2.20 (d, 1H, 5_(ax)-H), 2.37 (d, 2H, 2_(ax)- and5_(eq)-H's), 2.54 (d, 1H, 2_(eq)-H), 2.90 (br s, 1H, 1-H), 4.24 (br s,1H, 6-H), 5.08 (dd, 2H, CH₂Ar), 5.48 (d, 1H, NH), 5.62 (dd, 2H, 3- and4-H's), 7.35 (m, 5H, Ar H's).

[0222] (1S,2R,4R,5R)-2-Benzyloxycarbonylamino-4-iodo-7-oxo-6-oxabicyclo[3.2.1]octane(S1-5)

[0223] S1-4 (13.9 g, 50.5 mmol) was dissolved in dichloromethane (100mL) under N₂, 0.5 M NaHCO₃ (300 mL), KI (50.3 g, 303.3 mmol), and iodine(25.6 g, 101 mmol) were added and the mixture stirred at ambienttemperature for 72 h. The mixture was diluted with dichloromethane (50mL) and the organic phase separated. The organic phase was washed withsaturated aqueous Na₂S₂O₃ (2×50 mL), water (30 mL), and saturatedaqueous NaCl (20 mL), dried and evaporated to afford 16.3 g (80%) ofS1-5.

[0224]¹H NMR: (CDCl₃) δ 2.15 (m, 1H, 8_(ax)-H), 2.42 (m, 2H, 3_(ax)- and8_(eq)-H's), 2.75 (m, 2H, 1- and 3_(eq)-H's), 4.12 (br s, 1H, 2-H), 4.41(t, 1H, 4-H), 4.76 (dd, 1H, 5H), 4.92 (d, 1H, NH), 5.08 (dd, 2H, CH₂Ar),7.35 (m, 5H, Ar H's).

[0225] (1S,2R,5R)-2-Benzyloxycarbonylamino-7-oxo-6-oxabicyclo[3.2.1]oct-3-ene(S1-6).

[0226] S1-5 (4.0 g, 10 mmol) was dissolved in benzene (50 mL) under N₂.1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) (1.8 g, 12 mmol) was added andthe solution refluxed for 16 h. The precipitate was filtered and thefiltrate was diluted with EtOAc (200 mL). The filtrate was washed with 1M HCl (20 mL), saturated aqueous Na₂S₂O₃ (20 mL), water (20 mL), andsaturated aqueous NaCl (20 mL), dried and evaporated to give 2.2 g (81%)S1-6.

[0227]¹H NMR: (CDCl₃) δ 2.18 (d, 1H, 8_(ax)-H), 2.39 (m, 1H, 8_(eq)-H),3.04 (t, 1H, 1-H), 4.70 (m, 1H, 5-H), 4.82 (t, 1H, 2-H), 5.15 (dd, 3H,CH₂Ar and NH), 5.76 (d, 1H, 4-H), 5.92 (m, 1H, 3-H), 7.36 (s, 5H, ArH's).

[0228] (1 S,2R,5R)-Methyl2-Benzyloxycarbonylamino-5-hydroxycyclohex-3enecarboxylate (S1-7)

[0229] S1-6 (9.0 g, 33 mmol) was suspended in MeOH (90 mL) and cooled to0° C. NaOMe (2.8 g, 52.7 mmol) was added and the mixture stirred for 3 hduring which time a solution gradually formed. The solution wasneutralized with 2M HCl, diluted with saturated aqueous NaCl (200 mL),and extracted with dichloromethane (2×100 mL). The extracts werecombined, washed with water (20 mL) and saturated aqueous NaCl (20 ml),dried, and evaporated. The residue was flash chromatographed (silica gel(250 g), 50:50 hexane/EtOAc) to give 8.5 g (85%) of S1-7.

[0230]¹H NMR: (CDCl₃) δ 1.90 (m, 1H, 6_(ax)-H), 2.09 (m, 1H, 6_(eq)-H),2.81 (m, 1H, 1-H), 3.55 (s, 3H, CO₂Me), 4.15 (m, 1H, 5-H), 4.48 (t, 1H,2-H), 5.02 (dd, 2H, CH₂Ar), 5.32 (d, 1H, NH), 5.64 (dt, 1H, 4-H), 5.82(dt, 1H, 3-H), 7.28 (s, 5H, Ar H's).

[0231] (1S,2R,5S)-Methyl2-Benzyloxycarbonylamino-5-t-butoxycarbonylaminocyclohex-3-enecarboxylate(S1-8).

[0232] S1-7 (7.9 g, 25.9 mmol) was dissolved in dichloromethane (150 mL)and cooled to 0° C. under N₂. Triethylamine (6.3 g, 8.7 mL, 62.1 mmol)and methanesulfonyl chloride (7.1 g, 62.1 mmol) were added and themixture stirred at 0° C. for 2 h. (n-Bu)₄NN₃ (14.7 g, 51.7 mmol) indichloromethane (50 mL) was added and stirring continued at 0° C. for 3h followed by 15 h at ambient temperature. The mixture was cooled to 0°C. and P(n-Bu)₃ (15.7 g, 19.3 mL, 77.7 mmol) and water (1 mL)were addedand the mixture stirred at ambient temperature for 24 h. Di-tert-butyldicarbonate (17.0 g, 77.7 mmol) was added and stirring continued for 24h. The solvent was removed, the residue dissolved in 2:1 hexane/EtOAc(100 mL), the solution filtered, and evaporated. The residue was flashchromatographed (silica gel (240 g), 67:33 hexane/EtOAc) to give 5.9 g(56%) of S1-8.

[0233]¹H NMR: (CDCl₃) δ 1.40 (s, 9H, Boc H's), 1.88 (m, 1H, 6_(ax)-H),2.21 (m, 1H, 6_(eq)-H), 2.95 (m, 1H, 1-H), 3.60 (s, 3H, CO₂Me), 4.15 (d,1H, Boc NH), 4.50 (m, 2H, 2- and 5-H's), 5.02 (s, 2H, CH₂Ar), 5.38 (d,1H, Z NH), 5.65 (m, 2H, 3- and 4-H's), 7.30 (s, 5H, Ar H's).

[0234] (1R,2R,5S)-Methyl2-Benzyloxycarbonylamino-5-t-butoxycarbonylaminocyclohex-3-enecarboxylate(S1-9)

[0235] S1-8 (1.1 g, 2.7 mmol) was suspended in MeOH (50 mL). NaOMe (0.73g, 13.6 mmol) was added and the mixture refluxed for 18 h after which0.5 M NH₄Cl (50 mL) was added and the resulting precipitate collected.The filtrate was evaporated and the residue triturated with water (25mL). The insoluble portion was collected and combined with the originalprecipitate to give 0.85 g (77%) of S1-9.

[0236]¹H NMR: (CDCl₃) δ 1.38 (s, 9H, Boc H's), 1.66 (m, 1H, 6_(ax)-H),2.22 (d, 1H, 6_(eq)-H), 2.58 (t, 1H, 1-H), 3.59 (3, 3H, CO₂Me), 4.22 (brs, 1H, Boc NH), 4.50 (m, 2H, 2- and 5-H's), 4.75 (d, 1H, Z NH), 5.02 (s,2H, CH₂Ar), 5.62 (s, 2H, 3- and 4-H's), 7.30 (s, 5H, Ar H's).

[0237] (1R,2R,5S)-2-Benzyloxycarbonylamino-5-t-butoxycarbonylaminocyclohex-3-enecarboxylicAcid (S1-10)

[0238] S1-9 (0.85 g, 2.1 mmol) was suspended in 50:50MeOH/dichloromethane (5 mL) and cooled to 0° C. under N₂ after which 2MNaOH (2.0 mL) was added and the mixture stirred at ambient temperaturefor 16 h. The mixture was acidified with 2M HCl upon which a whiteprecipitate formed. The precipitate was collected, washed with water andhexane, and dried to give 0.74 g (90%) of S1-10.

[0239]¹H NMR: (CD₃OD) δ 1.42 (s, 9H, Boc H's), 1.66 (m, 1H, 6_(ax)-H),2.22 (d, 1H, 6_(eq)-H), 2.65 (t, 1H, 1-H), 4.18 (m, 1H, 5-H), 4.45 (m,1H, 5-H), 5.04 (s, 2H, CH₂Ar), 5.58 (m, 2H, 3- and 4-H's), 7.35 (s, 5H,Ar H's).

[0240] (1R,2R,5S)-2-Benzyloxycarbonylamino-5-t-butoxycarbonylamino-1-(2-trimethylsilyl)ethoxycarbonylaminocyclohex-3-ene(S1-11)

[0241] S1-10 (3.1 g, 7.9 mmol) was dissolved in THF (30 mL) under N₂ andcooled to 0° C. Triethylamine (1.6 g, 2.2 mL, 15.9 mmol) was addedfollowed by ethyl chloroformate (1.3 g, 1.5 mL, 11.8 mmol). The mixturewas stirred at 0° C. for 1 h. A solution of NaN₃ (1.3 g, 19.7 mmol) inwater (10 mL) was added and stirring at 0° C. was continued for 2 h. Thereaction mixture was partitioned between EtOAc (50 mL) and water (50mL). The organic phase was separated, dried, and evaporated. The residuewas dissolved in benzene (50 mL) and refluxed for 2 h.2-Trimethylsilylethanol (1.0 g, 1.2 mL, 8.7 mmol) was added and refluxcontinued for 3 h. The reaction mixture was diluted with EtOAc (200 mL),washed with saturated aqueous NaHCO₃ (50 mL), water (20 mL), andsaturated aqueous NaCl (20 mL), dried and evaporated. The residue wasflash chromatographed (silica gel (100 g), 67:33 hexane/EtOAc) to give3.1 g (77%) of S1-11.

[0242]¹H NMR: (CDCl₃) δ −0.02 (s, 9H, TMS), 0.90 (t, 3H, CH₂TMS), 1.40(s, 9H, Boc H's), 2.38 (m, 1H, 6_(eq)-H), 3.62 (m, 1H, 1-H), 4.08 (m,2H, OCH₂CH₂TMS), 4.18 (m, 1H), 4.38 (m, 1H), 4.62 (m, 1H), 5.07 (dd, 2H,CH₂Ar), 5.18 (m, 1H), 5.26 (m, 1H), 5.58 (d, 1H, olefinic H), 5.64 (d,2H, olefinic H), 7.30 (s, 5, Ar H's).

[0243] (1R,2R,5S)-2-Benzyloxycarbonylamino-1,5-diaminocyclohex-3-ene(S1-12)

[0244] S1-11 (2.5 g, 4.9 mmol) was added to TFA (10 mL) and the solutionstirred at ambient temperature for 16 h after which the solution wasevaporated. The residue was dissolved in water (20 mL), basified to pH14 with KOH and extracted with dichloromethane (3×50 mL). The extractswere combined, washed with water (20 mL), dried and evaporated to give1.1 g (85%) of S1-12.

[0245]¹H NMR: (CDCl₃) δ 1.30 (m, 1H, 6_(ax)-H), 2.15 (br d, 1H,6_(eq)-H), 2.68 (m, 1H, 1-H), 3.42 (br s, 1H, 5-H), 3.95 (m, 1H, 2-H),4.85 (d, 1H, Z NH), 5.08 (t, 2H, CH₂Ar), 5.45 (d, 1H, 4-H), 5.62 (d, 1H,3-H), 7.32 (s, 5H, Ar H's). ESCI MS m/e 262 M+1.

[0246] Di-(l)-menthylbicyclo[2.2.1]hept-5-ene-7-anti-(trimethylsilyl)-2-endo-3-exo-dicarboxylate(S4-26)

[0247] To a solution of S4-25 (6.09 g, 0.0155 mol) in toluene (100 mL)was added diethylaluminum chloride (8.6 mL of a 1.8 M solution intoluene) at −78° C. under nitrogen and the mixture was stirred for 1hour. To the resulting orange solution was added S2-14 (7.00 g, 0.0466mol) dropwise as a −78° C. solution in toluene (10 mL). The solution waskept at −78° C. for 2 hours, followed by slow warming to roomtemperature overnight. The aluminum reagent was quenched with asaturated solution of ammonium chloride (50 mL). The aqueous layer wasseparated and extracted with methylene chloride (100 mL) which wassubsequently dried over magnesium sulfate. Evaporation of the solventleft a yellow solid that was purified by column chromatography (10%ethyl acetate/hexanes) to give S4-26 as a while solid (7.19 g, 0.0136mol, 87% yield).

[0248]¹H NMR: (CDCl₃) δ −0.09 (s, 9H, SiMe₃), 0.74-1.95 (multiplets,36H, menthol), 2.72 (d, 1H, α-menthyl carbonyl CH), 3.19 (bs, 1H,bridgehead CH), 3.30 (bs, 1H, bridgehead CH), 3.40 (t, 1H, α-menthylcarbonyl CH), 4.48 (d of t, 1H, α-menthyl ester CH), 4.71 (d of t, 1H,α-menthyl ester CH), 5.92 (d of d, 1H, CH═CH), 6.19 (d of d, 1H, CH═CH).

[0249]5-exo-Bromo-3-exo-(1)-menthylcarboxybicyclo[2.2.1]heptane-7-anti(trimethylsilyl)-2,6-carbolactone(S4-27)

[0250] A solution of bromine (3.61 g, 0.0226 mol) in methylene chloride(20 mL) was added to a stirring solution of S4-26 (4.00 g, 0.00754 mol)in methylene chloride (80 mL). Stirring was continued at roomtemperature overnight. The solution was treated with 5% sodiumthiosulfate (150 mL), and the organic layer separated and dried overmagnesium sulfate. The solvent was evaporated at reduced pressure, andthe crude product purified by column chromatography (5% ethylacetate/hexanes) to give S4-27 as a white solid (3.53 g, 0.00754 mol,99% yield).

[0251]¹H NMR: (CDCl₃) δ −0.19 (s, 9H, SiMe₃), 0.74-1.91 (multiplets,18H, menthol), 2.82 (d, 1H, α-lactone carbonyl CH), 3.14 (bs, 1H,lactone bridgehead CH), 3.19 (d of d, 1H, bridgehead CH), 3.29 (t, 1H,α-menthyl carbonyl CH), 3.80 (d, 1H, α-lactone ester), 4.74 (d of t, 1H,α-menthyl ester CH), 4.94 (d, 1H, bromo CH).

[0252]Bicyclo[2.2.1]hept-5-ene-7-syn-(hydroxy)-2-exo-methyl-3-endo-(l)-menthyldicarboxylate (S4-28)

[0253] S4-27 (3.00 g, 0.00638 mol) was dissolved in anhydrous methanol(150 mL), silver nitrate (5.40 g, 0.0318 mol) added and the suspensionrefluxed for 3 days. The mixture was cooled, filtered through Celite andthe solvent evaporated to give an oily residue. Purification by columnchromatography gave S4-28 as a light yellow oil (1.72 g, 0.00491 mol,77% yield).

[0254]¹H NMR: (CDCl₃) δ 0.75-2.02 (multiplets, 18H, menthol), 2.83 (d,1H, α-menthyl carbonyl CH), 3.03 (bs, 1H, bridgehead CH), 3.14 (bs, 1H,bridgehead CH), 3.53 (t, 1H, α-methyl carbonyl CH), 3.76 (s, 3H, CH₃),4.62 (d of t, 1H, α-menthyl ester CH), 5.87 (d of d, 1H, CH═CH), 6.23 (dof d, 1H, CH═CH).

[0255]2-exo-Methyl-3-endo-(l)-menthylbicyclo[2.2.1]hept-5-ene-7-syn-(benzyloxy)dicarboxylate (S4-29)

[0256] Benzyl bromide (1.20 g, 0.0070 mol) and silver oxide (1.62 g,0.0070 mol) were added to a stirring solution of S4-28 (0.490 g, 0.00140mol) in DMF (25 mL). The suspension was stirred overnight and thendiluted with ethyl acetate (100 mL). The solution was washed repeatedlywith water followed by 1 N lithium chloride. The organic layer wasseparated and dried with magnesium sulfate. The solvent was evaporatedunder reduced pressure and the crude product was purified by columnchromatography on silica gel to give S4-29 as an oil (0.220g, 0.000500mol, 36% yield).

[0257]¹H NMR: (CDCl₃) δ 0.74-2.08 (multiplets, 18H, menthol), 2.83 (d,1H, α-menthyl carbonyl CH), 3.18 (bs, 1H, bridgehead CH), 3.44 (bs, 1H,bridgehead CH), 3.52 (t, 1H, bridge CH), 3.57 (s, 3H, CH₃), 3.68 (t, 1H,α-methyl carbonyl CH), 4.42 (d of d, 2H, benzyl —CH₂—), 4.61 (d of t,1H, α-menthyl ester CH), 5.89 (d of d, 1H, CH═CH), 6.22 (d of d, 1H,CH═CH), 7.25-7.38 (m, 5H, C₆H₅).

[0258]Bicyclo[2.2.1]hept-5-ene-7-syn-(benzyloxy)-2-exo-carboxy-3-endo-(l)-menthylcarboxylate (S4-30)

[0259] S4-29 (0.220 g, 0.00050 mol) was added to a mixture oftetrahydrofuran (1.5 mL), water (0.5 mL), and methanol (0.5 mL).Potassium hydroxide (0.036 g, 0.00065 mol) was added and the solutionstirred at room temperature overnight. The solvent was evaporated underreduced pressure and the residue purified by column chromatography (10%ethyl acetate/hexanes) to give S4-30 (0.050 g, 0.00012 mol, 23% yield).

[0260]¹H NMR: (CDCl₃) δ 0.73-2.01 (multiplets, 18H, menthol), 2.85 (d,1H, α-menthyl carbonyl CH), 3.18 (bs, 1H, bridgehead CH), 3.98 (bs, 1H,bridgehead CH), 3.53 (bs, 1H, bridge CH), 3.66 (t, 1H, α-methyl carbonylCH), 4.44 (d of d, 2H, benzyl —CH₂—), 4.63 (d of t, 1H, α-menthyl esterCH), 5.90 (d of d, 1H, CH═CH), 6.23 (d of d, 1H, CH═CH), 7.25-7.38 (m,5H, C₆H₅).

[0261] Mass Spec: calculated for C₂₆H₃₄O₅ 426.24; found 425.4 (M−1) and851.3 (2M−1).

[0262]Bicyclo[2.2.1]hept-5-ene-7-syn-(benzyloxy)-2-exo-(trimethylsilylethoxycarbonyl)-amino-3-endo-(l)-menthylCarboxylate (S4-31)

[0263] To a solution of S4-30 in benzene is added triethylamine anddiphenylphosphoryl azide. The solution is refluxed for 24 hours thencooled to room temperature. Trimethylsilylethanol is added, and thesolution refluxed for an additional 48 hours. The benzene solution ispartitioned between ethyl acetate and 1 M sodium bicarbonate. Theorganic layers are combined, washed with 1 M sodium bicarbonate anddried over sodium sulfate. The solvent is evaporated under reducedpressure to give the crude Curtius reaction product.

[0264]Bicyclo[2.2.1]heptane-7-syn-(benzyloxy)-2-exo-(trimethylsilylethoxycarbonyl)amino-3-endo-(l)-menthyl-5-exo-methyl-6-exo-methyltricarboxylate (S4-32)

[0265] S4-31, dry copper(II) chloride, 10% Pd/C, and dry methanol areadded to a flask with vigorous stirring. After degassing, the flask ischarged with carbon monoxide to a pressure just above 1 atm., which ismaintained for 72 hours. The solids are filtered and the residue workedup in the usual way to afford the biscarbonylation product.

[0266]Bicyclo[2.2.1]heptane-7-syn-(benzyloxy)-2-exo-(trimethylsilylethoxycarbonyl)amino-3-endo-(l)-menthylcarbox-5-exo-6-exo-dicarboxylicAnhydride (S4-33)

[0267] A mixture of S4-32, formic acid, and a catalytic amount ofp-toluenesulfonic acid is stirred at 90° C. overnight. Acetic anhydrideis added and the reaction mixture refluxed for 6 hours. Removal of thesolvents and washing with ether gives the desired anhydride.

[0268]Bicyclo[2.2.1]heptane-7-syn-(benzyloxy)-2-exo-(trimethylsilylethoxycarbonyl)-amino-3-endo-(l)-menthyl-6-exo-carboxy-5-exo-methylDicarboxylate (S4-33)

[0269] To a solution of S4-32 in equal amounts of toluene and carbontetrachloride is added quinidine. The suspension is cooled to −65° C.and stirred for 1 hour. Three equivalents of methanol are slowly addedover 30 minutes. The suspension is stirred at −65° C. for 4 daysfollowed by removal of the solvents under reduced pressure. Theresulting white solid is partitioned between ethyl acetate and 2M HCl.The quinine is recovered from the acid layer and S4-33 obtained from theorganic layer.

[0270]Bicyclo[2.2.1]heptane-7-syn-(benzyloxy)-2-exo-(trimethylsilylethoxycarbonyl)-amino-3-endo-(l)-menthyl-6-exo-(trimethylsilylethoxycarbonyl)amino-5-exo-methylDicarboxylate (S4-35)

[0271] To a solution of S4-34 in benzene is added triethylamine anddiphenylphosphoryl azide. The solution is refluxed for 24 hours. Aftercooling to room temperature, 2-trimethylsilylethanol is added and thesolution refluxed for 48 hours. The benzene solution is partitionedbetween ethyl acetate and 1 M sodium bicarbonate. The organic layers arecombined, washed with 1 M sodium bicarbonate, and dried over sodiumsulfate. The solvent is evaporated under reduced pressure to give thecrude Curtius reaction product.

[0272] endo-Bicyclo[2.2.1]hept-5-ene-2-benzylcarboxylate-3-carboxylicAcid (S5-37)

[0273] Compound S3-19 (4.00 g, 0.0244 mol) and quinidine (8.63 g, 0.0266mol) were suspended in equal amounts of toluene (50 mL) and carbontetrachloride (50 mL). The suspension was cooled to −55° C. after whichbenzyl alcohol (7.90 g, 0.0732 mol) was added over 15 minutes. Thereaction mixture became homogenous after 3 hours and was stirred at −55°C. for an additional 96 hours. After removal of the solvents, theresidue was partitioned between ethyl acetate (300 mL) and 2Mhydrochloric acid (100 mL). The organic layer was washed with water(2×50 mL) and saturated aqueous sodium chloride (1×50 mL). Drying overmagnesium sulfate and evaporation of the solvent gave S5-37 (4.17 g,0.0153 mol, 63% yield).

[0274]¹H NMR: (CDCl₃) δ 1.33 (d, 1H, bridge CH₂), 1.48 (d of t, 1H,bridge CH₂), 3.18 (bs, 1H, bridgehead CH), 3.21 (bs, 1H, bridgehead CH),3.33 (t, 2H, α-acid CH), 4.98 (d of d, 2H, CH₂Ph), 6.22 (d of d, 1H,CH═CH), 6.29 (d of d, 1H, CH═CH), 7.30 (m, 5H, C₆H₅).

[0275]2-endo-Benzylcarboxy-6-exo-iodobicyclo[2.2.1]heptane-3,5-carbolactone(S5-38)

[0276] S5-37 (4.10 g, 0.0151 mol) was dissolved in 0.5 M sodiumbicarbonate solution (120 mL) and cooled to 0° C. Potassium iodide (15.0g, 0.090 mol) and iodine (7.66 g, 0.030 mol) were added followed bymethylene chloride (40 mL). The solution was stirred at room temperatureovernight. After dilution with methylene chloride (100 mL), sodiumthiosulfate was added to quench the excess iodine. The organic layer wasseparated and washed with water (100 mL) and sodium chloride solution(100 mL). Drying over magnesium sulfate and evaporation of the solventgave S5-38 (5.44 g, 0.0137 mol, 91% yield).

[0277]¹H NMR: (CDCl₃) δ 1.86 (d of q, 1H, bridge —CH₂—), 2.47 (d of t,1H, bridge —CH₂—), 2.83 (d of d, 1H, α-lactone carbonyl CH), 2.93 (bs,1H, lactone bridgehead CH), 3.12 (d of d, 1H, α-benzyl ester CH), 3.29(m, 1H, bridgehead CH), 4.63 (d, 1H, α-lactone ester CH), 5.14 (d of d,2H, CH₂Ph), 5.19 (d, 1H, iodo CH), 7.38 (m, 5H, C₆H₅).

[0278] 2-endo-Benzylcarboxy-bicyclo[2.2.1]heptane-3,5-carbolactone(S5-39)

[0279] S5-38 (0.30 g, 0.75 mmol) was placed in DMSO under N₂, NaBH₄ (85mg, 2.25 mmol) added and the solution stirred at 850 C for 2 h. Themixture was cooled, diluted with water (50 mL) and extracted withdichloromethane (3×20 mL). The extracts were combined, washed with water(4×15 mL) and saturated aqueous NaCl (10 mL), dried, and evaporated togive 0.14 g (68%) of S5-39.

[0280] 5-endo-hydroxybicyclo[2.2.1]heptane-2-endo-benzyl-3-endo-methylDicarboxylate (S5-40)

[0281] Compound S5-39 is dissolved in methanol and sodium methoxideadded with stirring. Removal of the solvent gives S5-40.

[0282]Bicyclo[2.2.1]heptane-2-endo-benzyl-3-endo-methyl-5-exo-(t-butoxycarbonyl)aminoDicarboxylate (S5-41)

[0283] In a one-pot reaction S5-40 is converted to the correspondingmesylate with methanesulfonyl chloride, sodium azide added to displacethe mesylate to give exo-azide, which is followed by reduction withtributyl phosphine to give the free amine, which is protected as thet-Boc derivative to give S5-41.

[0284] Bicyclo[2.2.1]heptane-2-endo-carboxy-3-exo-methyl-5-exo-(t-butoxycarbonyl)aminoCarboxylate (S5-42)

[0285] The benzyl ether protecting group is removed by catalytichydrogenolysis of S5-41 with 10% Pd/C in methanol at room temperaturefor 6 hours. Filtration of the catalyst and removal of the solventyields crude S5-42.

[0286]Bicyclo[2.2.1]heptane-2-endo-carboxy-3-exo-methyl-5-exo-(t-butoxycarbonyl)aminoCarboxylate (S5-43)

[0287] Sodium is dissolved in methanol to generate sodium methoxide.S5-42 is added and the mixture stirred at 62° C for 16 hr. The mixtureis cooled and acetic acid added with cooling to neutralize the excesssodium methoxide. The mixture is diluted with water and extracted withethyl acetate. The extract is dried and evaporated to give S5-43.

[0288]Bicyclo[2.2.1]heptane-2-endo-benzyl-3-exo-methyl-5-exo-(t-butoxycarbonyl)aminoDicarboxylate (S5-44)

[0289] Compound S5-43 is reacted with benzyl bromide and cesiumcarbonate in tetrahydrofuran at room temperature to give benzyl esterS5-44, which is isolated by acid work-up of the crude reaction mixture.

[0290]Bicyclo[2.2.1]heptane-2-endo-benzyl-3-exo-carboxy-5-exo-(t-butoxycarbonyl)aminoCarboxylate (S5-45)

[0291] Compound S5-44 is dissolved in methanol and cooled to 0° C. underN₂. 2M NaOH (2 equivalents) is added dropwise, the mixture allowed tocome to ambient temperature and is stirred for 5 h. The solution isdiluted with water, acidified with 2M HCl and extracted with ethylacetate. The extract is washed with water, saturated aqueous NaCl, driedand evaporated to give S5-45.

[0292]Bicyclo[2.2.1]heptane-2-endo-benzyl-3-exo-(trimethylsilylethoxycarbonyl)amino-5-exo-(t-butoxycarbonyl)aminocarboxylate (S5-46)

[0293] To a solution of S5-45 in benzene is added triethylamine anddiphenylphosphoryl azide. The solution is refluxed for 24 hours and thencooled to room temperature. Trimethylsilylethanol is added and thesolution refluxed for 48 hours. The solution is partitioned betweenethyl acetate and 1 M sodium bicarbonate. The organic layer is washedwith 1 M sodium bicarbonate and dried over sodium sulfate. The solventis evaporated under reduced pressure to give crude Curtius productS5-46.

[0294]endo-Bicyclo[2.2.1]hept-5-ene-2-(4-methoxy)benzylcarboxylate-3-carboxylicAcid (S6-48)

[0295] Compound S3-19 and quinidine are suspended in equal amounts oftoluene and carbon tetrachloride and cooled to −55° C. p-Methoxybenzylalcohol is added over 15 minutes and the solution stirred at −55° C. for96 hours. After removal of the solvents, the residue is partitionedbetween ethyl acetate and 2 M hydrochloric acid. The organic layer iswashed with water and saturated aqueous sodium chloride. Drying overmagnesium sulfate and removal of the solvent gives S6-48.

[0296]endo-Bicyclo[2.2.1]hept-5-ene-2-(4-methoxy)benzyl-3-(trimethylsilylethoxycarbonyl)aminoCarboxylate (S6-49)

[0297] To a solution of S6-48 in benzene is added triethylamine anddiphenylphosphoryl azide. The solution is refluxed for 24 hours, cooledto room temperature, trimethylsilylethanol is added, and the solution isrefluxed for an additional 48 hours. The benzene solution is partitionedbetween ethyl acetate and 1 M sodium bicarbonate. The organic layers arecombined, washed with 1 M sodium bicarbonate, and dried with sodiumsulfate. The solvent is evaporated under reduced pressure to give crudeCurtius product S6-49.

[0298]Bicyclo[2.2.1]heptane-2-endo-(4-methoxy)benzyl-3-endo(trimethylsilylethoxycarbonyl)amino-5-exo-methyl-6-exo-methylTricarboxylate (S6-50).

[0299] S6-49, copper(II) chloride, 10% Pd/C, and dry methanol are addedto a flask with vigorous stirring. After degassing the suspension, theflask is charged with carbon monoxide to a pressure just above 1 atm.The pressure of carbon monoxide is maintained over 72 hours. The solidsare filtered off, and the crude reaction mixture worked up in the usualway to afford S6-50.

[0300]Bicyclo[2.2.1]heptane-2-endo-(4-methoxy)benzyl-3-endo(trimethylsilylethoxycarbonyl)amino-5-exo-6-exo-dicarboxylicAnhydride (S6-51).

[0301] S6-50, formic acid, and a catalytic amount of p-toluenesulfonicacid is heated at 90° C. overnight. Acetic anhydride is added to thereaction mixture, and it is refluxed for an additional 6 hours. Removalof the solvents and washing with ether affords S6-51.

[0302]Bicyclo[2.2.1]heptane-2-endo-(4-methoxy)benzyl-3-endo-(trimethylsilylethoxycarbonyl)amino-5-exo-carboxy-6-exo-methylDicarboxylate (S6-52).

[0303] To a solution of S6-51 in equal amounts of toluene and carbontetrachloride is added quinine. The suspension is cooled to −65° C. andstirred for 1 hour. Three equivalents of methanol are added slowly over30 minutes. The suspension is stirred at −65° C. for 4 days followed byremoval of the solvents. The resulting white solid is partitionedbetween ethyl acetate and 2 M HCl, with S6-52 worked up from the organiclayer.

[0304] Bicyclo[2.2.1]heptane-2-endo-(4-methoxy)benzyl-3-endo(trimethylsilylethoxycarbonyl)amino-5-exo-(trimethylsilylethoxycarbonyl)amino-6-exo-methylDicarboxylate (S6-53).

[0305] To a solution of S6-52 in benzene is added triethylamine anddiphenylphosphoryl azide. The solution is refluxed for 24 hours thencooled to room temperature. 2-Trimethylsilylethanol is added, and thesolution is refluxed for an additional 48 hours. The benzene solution ispartitioned between ethyl acetate and 1 M sodium bicarbonate. Theorganic layers are combined, washed with 1 M sodium bicarbonate, anddried with sodium sulfate. The solvent is evaporated under reducedpressure to give S6-53.

[0306]Bicyclo[2.2.1]heptane-2-exo-(4-methoxy)benzyl-3-endo-(trimethylsilylethoxycarbonyl)amino-5-exo-(trimethylsilylethoxycarbonyl)amino-6-endo-methylDicarboxylate (S6-54).

[0307] To a solution of S6-53 in tetrahydrofuran is carefully addedpotassium tertbutoxide. The basic solution is refluxed for 24 hoursfollowed by addition of acetic acid. Standard extraction methods givethe double epimerized product S6-54.

[0308] To 0.300 g R,R-1,2-trans-diaminocyclohexane (2.63 mmol) in 5 mLCH₂Cl₂ at 0° C. was added 0.600 g of 2,6-diformyl-4-bromophenol (2.62mmol) in 5 mL of CH₂Cl₂. The yellow solution was allowed to warm to roomtemperature and stirred for 48 hours. The reaction solution wasdecanted, and added to 150 mL of methanol. After standing for 30minutes, the yellow precipitate was collected, washed with methanol, andair-dried (0.580 mg; 72% yield).

[0309]¹H NMR (400 MHz, CDCl₃) δ 14.31 (s, 3H, OH), 8.58 (s, 3H, CH═N),8.19 (s, 3H, CH═N), 7.88 (d, 3H, J=2.0 Hz, ArH), 7.27 (d, 3H, J=2.0 Hz,ArH), 3.30-3.42 (m, 6H, CH₂-CH-N), 1.41-1.90 (m, 24H, aliphatic).

[0310] MS (FAB): Calcd for C₄₂H₄₆N₆O₃Br₃ 923.115; found 923.3 [M+H]⁺.

[0311] To 0.300 g R,R-1,2-trans-diaminocyclohexane (2.63 mmol) in 6 mLCH₂Cl₂ at 0° C. was added 0.826 g of2,6-diformyl-4-(1-dodec-1-yne)phenol (2.63 mmol) in 6 mL of CH₂Cl₂. Theorange solution was stirred at 0° C. for 1 hour and then allowed to warmto room temperature after which stirring was continued for 16 hours. Thereaction solution was decanted and added to 150 mL of methanol. A stickyyellow solid was obtained after decanting the methanol solution.Chromatographic cleanup of the residue gave a yellow powder.

[0312]¹H NMR (400 MHz, CDCl₃) δ 14.32 (s, 3H, OH), 8.62 (s, 3H, CH═N),8.18 (s, 3H, CH═N), 7.84 (d, 3H, J=2.0 Hz, ArH), 7.20 (d, 3H, J=2.0 Hz,ArH), 3.30-3.42 (m, 6H, CH₂-CH-N), 2.25 (t, 6H, J=7.2 Hz, propargylic),1.20-1.83 (m, 72H, aliphatic), 0.85 (t, 9H, J=7.0 Hz, CH₃).

[0313]¹³C NMR (400 MHz, CDCl₃) δ 163.4, 161.8, 155.7, 136.9, 132.7,123.9, 119.0, 113.9, 88.7, 79.7, 75.5, 73.2, 33.6, 33.3, 32.2, 29.8,29.7, 29.6, 29.4, 29.2, 29.1, 24.6, 24.5, 22.9, 19.6, 14.4.

[0314] MS (FAB): Calcd for C₇₈H₁₀₉N₆O₃ 1177.856; found: 1177.8 [M+H]⁺.

[0315] To 0.240 g of 2,6-diformyl-4-(1-dodecene)phenol (0.76 mmol) in 10mL of benzene was added a 10 mL benzene solution ofR,R-1,2-trans-diaminocyclohexane (0.087g, 0.76 mmol). The solution wasstirred at room temperature for 48 hours shielded from the light. Theorange solution was taken to dryness and chromatographed (silica, 50/50acetone/Et₂O) to give a yellow sticky solid (33% yield).

[0316]¹H NMR (400 MHz, CDCl₃) δ 14.12 (s, 3H, OH), 8.62 (s, 3H, CH═N),8.40 (s, 3H, CH═N), 7.82 (d, 3H, J=2.0 Hz, ArH), 7.28 (d, 3H, J=2.0 Hz,ArH), 6.22 (d, 3H, vinyl), 6.05 (d, 3H, vinyl), 3.30-3.42 (m, 6H,CH₂-CH-N), 1.04-1.98(m, 87H, aliphatic).

[0317] MS (FAB): Calcd for C₇₈H₁₁₅N₆O₃ 1183.90; found: 1184.6 [M+H]⁺.

[0318] Triethylamine (0.50 mL, 3.59 mmol) andR,R-1,2-transdiaminocyclohexane (0.190 g, 1.66 mmol) were combined in150 mL EtOAc and purged with N₂ for 5 minutes. To this solution wasadded 0.331 g isophthalolyl chloride (1.66 mmol) dissolved in 100 mLEtOAc dropwise over six hours. The solution was filtered and thefiltrate taken to dryness. TLC (5% methanol/CH₂Cl₂) shows the productmixture to be primarily composed of two macrocycles. Chromatographicseparation (silica, 5% methanol/CH₂Cl₂) gave the above tetramer (0.020g, 5% yield) and hexamer (about 10%).

[0319] Tetramer:

[0320]¹H NMR (400 MHz, CDCl₃) δ 7.82 (s, 1H), 7.60 (br s, 2H), 7.45 (brs, 2H), 7.18 (br s, 1H), 3.90 (br s, 2H), 2.22 (d, 2H), 1.85 (m, 4H),1.41 (m, 4H).

[0321] MS (ESI): Calcd for C₂₈H₃₃N₄O₄ 489.25; found 489.4 [M+H]⁺.

[0322] Hexamer:

[0323] MS (ESI): Calcd for C₄₂H₄₉N₆O₆ 733.37; found 733.5 [M+H]⁺.

CONCLUSION

[0324] Thus, it will be appreciated that the present invention providesversatile synthons and modules for use in the formation ofnanomembranes. Methods for the preparation of the synthons, for thelinking together of synthons to form modules, in particular modules inwhich the ring of synthons define a pore in the resulting module, andfor the connection of modules to form nanomembranes are also provided.The nanomembranes are useful, among other things, as filters.

[0325] Although certain embodiments and examples have been used todescribe the present invention, it will be apparent to those skilled inthe art that changes in the embodiments and examples shown may be madewithout departing from the scope and spirit of this invention.

[0326] Other embodiments are within the following claims.

What is claimed:
 1. An amphiphilic module, comprising: 3-24 synthonsindependently selected from the group consisting of aryl, heteroaryl,alicyclic and heteroalicyclic, provided at least one of the synthons isdifferent from the others, wherein: a first synthon is bonded to asecond synthon through a linker; the second synthon is bonded to a thirdsynthon through a second linker; the third synthon is bonded to a fourthsynthon, if four synthons are desired in the module, the fourth to afifth, etc., until an n^(th) synthon is bonded to its predecessorthrough an (n−1)^(th) linker where n is 4-24; and, the n^(th) synthon isbonded to the first synthon through an n^(th) linker to form a closedring of synthons; 1 or more lipophilic moieties bonded to one or more ofthe synthons; and, 1 or more hydrophilic moieties bonded to one or moreof the synthons.
 2. The amphiphilic module of claim 1, wherein eachsynthon is independently selected from the group consisting of benzene,naphthalene, anthracene, phenylene, phenathracene, pyrene, triphenylene,phenanthrene, pyridine, pyrimidine, pyridazine, biphenyl, bipyridyl,cyclohexane, cyclohexene, decaline, piperidine, pyrrolidine,tetrahydropyran, tetranhydrothiane, 1,3-dioxane, 1,3-dithiane,1,3-diazane, tetrahydrothiophene, tetrahydrofuran, pyrrole,cyclopentane, triptycene, adamantane, bicyclo[2.2.1]heptane,bicyclo[2.2.1]heptene, 7-azabicyclo[2.2.1]heptane,1,3-diazabicyclo[2.2.1]heptane, bicyclo[2.2.2]octane,bicyclo[2.2.2]octene, bicyclo[3.3.0]octane, bicyclo[3.3.1]nonane,bicyclo[3.3.1]nonene, bicyclo[4.2.2]decane or bicyclo[4.2.2]decene. 3.The amphiphilic module of claim 1, wherein the lipophilic moiety isselected from the group consisting of -(8C-28C)alkyl, —O(8C-28C)alkyl,—NH(8C-28C)alkyl, —OC(O)-(8C-28C)alkyl, —C(O)O-(8C-28C)alkyl,—NHC(O)-(8C-28C)alkyl, —C(O)NH-(8C-28C)alkyl, —CH═CH-(8C-28C)alkyl and—C≡C-(8C-28C)alkyl, wherein the carbon atoms of the (8C-28C)alkyl groupmay be interrupted by one or more —S—, double bond, triple bond or—SiR′R″— groups, substituted with one or more fluorine atoms or anycombination of these; R′ and R″ independently comprise (1C-18C)alkyl. 4.The amphiphilic module of claim 1, wherein the hydrophilic moiety isselected from the group consisting of —OH, —OCH₃, —NH₂, —C≡N, —NO₂,—⁺NRR′R″, —SO₃ ⁻, —OPO₂ ²—, —OC(O)CH═CH₂, —SO₂NH₂, SO₂N RR′,—OP(O)(OCH₂CH₂N⁺RR′R″)O⁻, —C(O)OH, —C(O)O⁻, guanidinium, aminate,pyridinium, —C(O)OCH₃, —C(O)OCH₂CH₃, —C(O)OCH═CH₂, —O(CH₂)_(y)C(O)NH₂,—O(CH₂CH₂O)_(z)R′″ and

wherein R, R′ and R″ are independently selected from the groupconsisting of hydrogen and (1 C-4C)alkyl, R′″ is selected from the groupconsisting of hydrogen, —CH₂C(O)OH and —CH₂C(O)NH₂ wherein y is 1-6 andz is 1-50.
 5. The amphiphilic module of claim 1, wherein each linker isindependently selected from the group consisting of —O—, —S—, —NR¹⁷—,—SS—, —(CR¹⁷R¹⁸)_(m)—, —CH(OH)—, —C(OH)R¹⁷-CH₂NR¹⁸—, —C(OH)CH(NHR¹⁷)—,—CR¹⁷═CR¹⁸—, —C≡C—, —C(O)O—, —C(O)S—, —OC(O)O—, C(O)NR¹⁷—, —CR¹⁷═N—,—CR¹⁷═NNH—, —NHC(O)O—, —NHC(O)NR¹⁷—, —CH(OH)CH₂(CO₂R¹⁷)—, —CH═CR¹⁷C(O)—,—C≡C—C≡C—, —C(CHR¹⁷R¹⁸)S—,

—C(CH(CH₃)₂)Si(CH₃)₂—, —C(O)CH₂(CO₂R¹⁷)—, and

wherein R¹⁷ and R¹⁸ are independently selected from the group consistingof hydrogen, (1 C-4C)alkyl and a group that confers a selected chemicalor physical characteristic, or a combination thereof, on the module. 6.The amphiphilic module of claim 1, wherein every other synthon is thesame; that the first, third, and if present, fifth, seventh, etc.,synthons are the same and the second, and if present, the fourth, sixth,eighth, etc., synthons are the same.
 7. The amphiphilic module of claim6, wherein all the linkers are the same.
 8. The amphilphilic module ofclaim 7, comprising 12 synthons.
 9. The amphiphilic module of claim 7,comprising 10 synthons.
 10. The amphiphilic module of claim 7,comprising 8 synthons.
 11. The amphiphilic module of claim 7, comprising6 synthons.
 12. The amphiphilic module of claim 7, comprising 4synthons.
 13. The amphiphilic module of claim 1, comprising the formula:

wherein: A₁-A₈ are synthons; L₁-L₈ are linkers; one or more of R₁, R₃,R₅, R₇, R₉, R₁₁, R₁₃ and R₁₅ comprises a lipophilic group, which may besame as, or different from, each other; one or more of R₂, R₄, R₆, R₈,R₁₀, R₁₂, R₁₄ and R₁₆ comprises a hydrophilic group, which may be thesame as, or different from, each other; each R group that is not alipophilic or a hydrophilic group is independently either absent orcomprises a group that confers a selected chemical or physicalcharacteristic or combination thereof on the module; and, each A andeach L may optionally be bonded to one or more additional substituentsthat confer selected chemical or physical characteristics orcombinations thereof on the module.
 14. The amphiphilic module of claim13, wherein A₁, A₃, A₅ and A₇ comprise a first synthon.
 15. Theamphiphilic module of claim 14, wherein A₂, A4, A₆ and A₈ comprise asecond synthon, which is different from the first synthon.
 16. Theamphiphilic module of claim 15, wherein all the linkers are the same.17. An amphiphilic module, comprising the chemical structure:

wherein: X and Y are independently hydrogen, —OC(O)CH═CH₂,—NHC(O)CH═CH₂,

—SH or —NH₂; or, X is —C(O)OH, —C(O)OCH₃, —C(O)Cl or another activatedacid and Y is —NH₂, —OH or —SH; R₁ is selected from the group consistingof —CH₂—(10C-18C)alkyl, —CH═CH-(10C-18C)alkyl, —C≡C-(10C-18C)alkyl,—OC(O)-(10C-18C)alkyl, —C(O)O-(10C-18C)alkyl, —NHC(O)-(10C-18C)alkyl,—C(O)NH-(10C-18C)alkyl and —O-(10C-18C)alkyl; one or more of R₂, R₃, R₄and R₅ are independently selected from the group consisting of hydrogen,—C(O)(CH₂)₂C(O)OCH₃, —C(O)CH═CH₂,

and

 wherein n1 is 1-50 and n2 is 1-4, provided that at least one of R₂, R₃or R₄ must be other than hydrogen; and, L is selected from the groupconsisting of —C(O)O—, —C(O)NH—, —CH₂NH— and —CH═N—, wherein the oxygenor nitrogen is bonded to either the benzene ring or the cyclohexyl ring.18. The amphiphilic module of claim 17, wherein the nitrogen or oxygenof the L group is bonded to the cyclohexyl group.
 19. The amphiphilicmodule of claim 17, wherein the nitrogen or oxygen of the L groupalternates, that is, if a nitrogen or oxygen of an L group is bonded tothe cyclohexyl ring, the nitrogen or oxygen of the next L group goingaround the ring is bonded to the benzene ring.
 20. An amphiphilicmodule, comprising the chemical structure:

wherein: Z is —NZ₁- or —CZ₂Z₃, wherein Z₁ is selected from the groupconsisting of hydrogen, an amino acid residue and —C(O)CH═CH₂; Z₂ ishydrogen and Z₃ is selected from the group consisting of hydrogen, —OH,—NH₂ and —SH, or one of Z₂ or Z₃ is selected from the group consistingof hydrogen, —OH, —NH₂, —SH, —(CH₂)_(z4)OH, —(CH₂)_(z4)NH₂ and—(CH₂)_(z4)SH and the other is selected from the group consisting of—(CH₂)_(z4)OH, —(CH₂)_(z4)NH₂ and —(CH₂)_(z4)SH, wherein Z₄ is 1, 2, 3or 4; R₁ is selected from the group consisting of CH₂-(10C-18C)alkyl,—CH═CH-(10C-18C)alkyl, —C≡C-(10C-18C)alkyl, —OC(O)-(10C-18C)alkyl,—C(O)O-(10C-18C)alkyl, —NHC(O)-(10C-18C)alkyl, —C(O)NH-(10C-18C)alkyland —O-(10C-18C)alkyl; one or more of R₂, R₃, R₄ and R₅ areindependently selected from the group consisting of hydrogen,—C(O)(CH₂)₂C(O)OCH₃, —C(O)CH═CH₂,

and

 wherein n1 is 1-50 and n2 is 1-4, provided that at least one of R₂, R₃or R₄ must be other than hydrogen; and, L is selected from the groupconsisting of —C(O)O—, —C(O)NH—, —CH₂NH— and —CH═N—, wherein the oxygenor nitrogen is bonded to either the benzene ring or the cyclohexanering.
 21. The amphiphilic module of claim 20, wherein the nitrogen oroxygen of the L group is bonded to the cyclohexyl ring.
 22. Theamphiphilic module of claim 20, wherein the nitrogen or oxygen of the Lgroup alternates, that is, if a nitrogen or oxygen of an L group isbonded to the cyclohexyl ring, the nitrogen or oxygen of the next Lgroup going around the ring is bonded to the benzene ring.
 23. Anamphiphilic module, comprising the chemical structure:

wherein: X and Y are independently hydrogen,

—OC(O)CH═CH₂, —NHC(O)CH═CH₂, —SH or —NH₂; or, X is —C(O)OH, —C(O)OCH₃,—C(O)Cl or another activated acid and Y is —NH₂, —OH or —SH; when X andY are both hydrogen or —C(O)OCH₃, R₁ is selected from the groupconsisting of —CH═CH₂, —OC(O)CH═CH₂ and —NHC(O)CH═CH₂; when X and Y areboth —SH or —NH₂ or X is —C(O)OCH₃ and Y is —NH₂, R₁ is hydrogen; R₆ isselected from the group consisting of CH₂-(10C-18C)alkyl,—CH═CH-(10C-18C)alkyl, —C≡C-(10C-18C)alkyl, —OC(O)-(10C-18C)alkyl,—C(O)O-(10C-18C)alkyl, —NHC(O)-(10C-18C)alkyl, —C(O)NH-(10C-18C)alkyland —O-(10C-18C)alkyl; one or more of R₂, R₃, R₄ and R₅ areindependently selected from the group consisting of hydrogen,—C(O)(CH₂)₂C(O)OCH₃, —C(O)CH═CH₂,

and

 wherein n1 is 1-50 and n2 is 1-4, provided that at least one of R₂, R₃or R₄ must be other than hydrogen; and, L is selected from the groupconsisting of —C(O)O—, —C(O)NH—, —CH₂NH— and —CH═N—, wherein the oxygenor nitrogen is bonded to either the benzene ring or thebicyclo[2.2.1]heptane ring.
 24. The amphiphilic module of claim 23,wherein the nitrogen or oxygen of the L group is bonded to thebicyclo[2.2.1]heptane ring.
 25. The amphiphilic module of claim 23,wherein the nitrogen or oxygen of the L group alternates, that is, if anitrogen or oxygen of an L group is bonded to the bicyclo[2.2.1]heptanering, the nitrogen or oxygen of the next L group going around the ringis bonded to the benzene ring.
 26. The amphiphilic module of claim 1,comprising the structure:

wherein: A₁-A₆ are the synthons; L₁-L₆ are the linkers; one or more ofR₁, R₃, R₅, R₇, R₉ and R₁₁ comprises a lipophilic group, which may besame as, or different from, each other; One or more of R₂, R₄, R₆, R₈,R₁₀ and R₁₂ comprises a hydrophilic group, which may be the same as, ordifferent from, each other; each R group that is not a lipophilic or ahydrophilic group is independently either absent or comprises a groupthat confer a selected chemical or physical characteristic orcombination thereof on the module; and, each A and each L may optionallybe bonded to one or more additional substituents that confer selectedchemical or physical characteristics or combinations thereof on themodule.
 27. The amphiphilic module of claim 26, wherein A₁, A₃ and A₅comprise a first synthon.
 28. The amphiphilic module of claim 27,wherein A₂, A₄ and A₆ comprise a second synthon, which is different fromthe first synthon.
 29. The amphiphilic module of claim 28, wherein allthe linkers are the same.
 30. An amphiphilic module comprising thestructure:

wherein: X and Y are both —SH or —NH₂; or, X is —C(O)OH, —C(O)OCH₃,—C(O)Cl or another activated acid and Y is —NH₂; R₁ is selected from thegroup consisting of —CH₂—(10C-18C)alkyl, —CH═CH-(10C-18C)alkyl,—C≡C-(10C-18C)alkyl, —OC(O)-(10C-18C)alkyl, —C(O)O-(10C-18C)alkyl,—NHC(O)-(10C-18C)alkyl, —C(O)NH-(10C-18C)alkyl and —O-(10C-18C)alkyl;R₂, R₃ and R₄ are independently selected from the group consisting ofhydrogen, —C(O)(CH₂)₂C(O)OCH₃, —C(O)CH═CH₂,

and

 wherein n1 is 1-50 and n2 is 1-4, provided that at least one of R₂, R₃or R₄ must be other than hydrogen; and, L is selected from the groupconsisting of —C(O)O—, —C(O)NH—, —CH₂NH— and —CH═N—, wherein the oxygenor nitrogen is bonded to either the benzene ring or the cyclohexyl ring.31. The amphiphilic module of claim 30, wherein the nitrogen or oxygenof the L group is bonded to the cyclohexyl ring.
 32. The amphiphilicmodule of claim 30, wherein the nitrogen or oxygen of the L groupalternates, that is, if a nitrogen or oxygen of an L group is bonded tothe cyclohexyl ring, the nitrogen or oxygen of the next L group goingaround the ring is bonded to the benzene ring.
 33. An amphiphilicmodule, comprising the chemical structure:

wherein: X and Y are independently hydrogen,

—OC(O)CH═CH₂, —NHC(O)CH═CH₂, —SH or —NH₂; or, X is —C(O)OH, —C(O)OCH₃,—C(O)Cl or another activated acid and Y is —NH₂, —OH or —SH; when X andY are both hydrogen or —C(O)OCH₃, R₁ is selected from the groupconsisting of —CH═CH₂, —OC(O)CH═CH₂ and —NHC(O)CH═CH₂; when X and Y areboth —SH or —NH₂ or X is —C(O)OCH₃ and Y is —NH₂, R₁ is hydrogen; R₅ isselected from the group consisting of CH₂-(10C-18C)alkyl,—CH═CH-(10C-18C)alkyl, —C≡C-(10C-18C)alkyl, —OC(O)-(10C-18C)alkyl,—C(O)O-(10C-18C)alkyl, —NHC(O)-(10C-18C)alkyl, —C(O)NH-(10C-18C)alkyland —O-(10C-18C)alkyl; R₂, R₃ and R₄ are independently selected from thegroup consisting of hydrogen, —C(O)(CH₂)₂C(O)OCH₃, —CH₂C(O)CH═CH₂,

and

 wherein n1 is 1-50 and n2 is 1-4, provided that at least one of R₂, R₃or R₄ must be other than hydrogen; and, L is selected from the groupconsisting of —C(O)O—, —C(O)NH—, —CH₂NH— and —CH═N—, wherein the oxygenor nitrogen is bonded to either the benzene ring or thebicyclo[2.2.1]heptane ring.
 34. The amphiphilic module of claim 33,wherein the nitrogen or oxygen of the L group is is bonded to thebicyclo[2.2.1]heptane ring.
 35. The amphiphilic module of claim 33,wherein the nitrogen or oxygen of the L group alternates, that is, if anitrogen or oxygen of an L group is bonded to the bicyclo[2.2.1]heptanering, the nitrogen or oxygen of the next L group going around the ringis bonded to the benzene ring.
 36. An amphiphilic module, comprising thechemical structure:

wherein: X and Y are independently hydrogen,

—OC(O)CH═CH₂, —NHC(O)CH═CH₂, —SH or —NH₂; or, X is —C(O)OH, —C(O)OCH₃,—C(O)Cl or another activated acid and Y is —NH₂, —OH or —SH; R₁ isselected from the group consisting of —CH₂-(10C-18C)alkyl,—CH═CH-(10C-18C)alkyl, —C≡C-(10C-18C)alkyl, —OC(O)-(10C-18C)alkyl,—C(O)O-(10C-18C)alkyl, —NHC(O)-(10C-18C)alkyl, —C(O)NH-(10C-18C)alkyland —O-(10C-18C)alkyl; R₂, R₃ and R₄ are independently selected from thegroup consisting of hydrogen, —C(O)(CH₂)₂C(O)OCH₃, —C(O)CH═CH₂,

and

 wherein n1 is 1-50 and n2 is 1-4, provided that at least one of R₂, R₃or R₄ must be other than hydrogen; and, L is selected from the groupconsisting of —C(O)O—, —C(O)NH—, —CH₂NH— and —CH═N—, wherein thenitrogen or oxygen is bonded to either the benzene ring or thecyclohexyl ring.
 37. The amphiphilic module of claim 36, wherein thenitrogen or oxygen of the L group is bonded to the cyclohexyl ring. 38.The amphiphilic module of claim 36, wherein the nitrogen or oxygen ofthe L group alternates, that is, if a nitrogen or oxygen of an L groupis bonded to the cyclohexyl ring, the nitrogen or oxygen of the next Lgroup going around the ring is bonded to the benzene ring.
 39. Anamphiphilic module, comprising the chemical structure:

wherein: X and Y are independently hydrogen,

—OC(O)CH═CH₂, —NHC(O)CH═CH₂, —SH or —NH₂; or, X is —C(O)OH, —C(O)OCH₃,—C(O)Cl or another activated acid and Y is —NH₂, —OH or —SH; when X andY are both hydrogen or —C(O)OCH₃, R₁ is selected from the groupconsisting of —CH═CH₂, —OC(O)CH═CH₂ and —NHC(O)CH═CH₂; when X and Y areboth —SH or —NH₂ or X is —C(O)OCH₃ and Y is —NH₂, R₁ is hydrogen; R₅ isselected from the group consisting of CH₂-(10C-18C)alkyl,—CH═CH-(10C-18C)alkyl, —C≡C-(10C-18C)alkyl, —OC(O)-(10C-18C)alkyl,—C(O)O-(10C-18C)alkyl, —NHC(O)-(10C-18C)alkyl, —C(O)NH-(10C-18C)alkyland —O-(10C-18C)alkyl; R₂, R₃ and R₄ are independently selected from thegroup consisting of hydrogen, —C(O)(CH₂)₂C(O)OCH₃, —C(O)CH═CH₂,

and

 wherein n1 is 1-50 and n2 is 1-4, provided that at least one of R₂, R₃or R₄ must be other than hydrogen; and, L is selected from the groupconsisting of —C(O)O—, —C(O)NH—, —CH₂NH— and —CH═N—, wherein the oxygenor nitrogen is bonded to either the benzene ring or thebicyclo[2.2.1]heptane ring.
 40. The amphiphilic module of claim 39,wherein the nitrogen or oxygen of the L group is bonded to thebicyclo[2.2.1]heptane ring.
 41. The amphiphilic module of claim 39,wherein the nitrogen or oxygen of the L group alternates, that is, if anitrogen or oxygen of an L group is bonded to the cyclohexyl ring, thenitrogen or oxygen of the next L group going around the ring is bondedto the benzene ring.
 42. A method of synthesizing an amphiphilic moduleof any one of claims 1, 17, 20, 23, 30, 33, 36 or 39, comprising:providing a plurality of first synthons comprising two functional groupsthat may be the same or different; providing a plurality of secondsynthons, which are different than the first synthons, comprising twofunctional groups that may be the same or different; wherein thefunctional groups of the first synthons can only react with thefunctional groups of the second synthons; contacting the first andsecond synthons in a solvent; and, isolating the amphiphilic module. 43.The method of claim 42, further comprising a reagent or reagents thatcatalyzes the reaction of the functional groups of the first synthonwith the functional groups of the second synthon.
 44. A method forsynthesizing an amphiphilic module of any one of claims 1, 17, 20, 23,30, 33, 36 or 39, comprising: placing a first synthon comprising afunctional group in a solvent; adding a second synthon comprising afunctional group that reacts with the functional group of the firstsynthon to form a dimer; adding a third synthon, which may be the sameas, or different from, the first synthon and which comprises afunctional group that reacts with a second functional group of thesecond synthon to form a trimer; repeating the above steps until an nthsynthon is added, the nth synthon comprising a functional group thatreacts with a second functional group of the first synthon to form aring, wherein n is 1-24.
 45. The method of claim 44, wherein a reagentor reagents is added to catalyze the reaction of a functional group of asynthon with a functional group of the next synthon being added or whichitself reacts with a functional group of a synthon to form anintermediate which then reacts with a functional group of the nextsynthon being added to form a bond.
 46. A two-dimensional array,comprising a plurality of amphiphilic modules wherein each module isbonded to one or more adjacent modules by one or more connectors betweeneach pair of adjacent modules.
 47. The two-dimensional array of claim46, wherein the each connector is independently selected from the groupconsisting of —O—, —S—, —NR¹⁹—, —SS—, —(CR¹⁹R²⁰)_(m)—, —CH(OH)—,—C(OH)R¹⁹—CH₂NR²⁰—, —C(OH)CH(NHR¹⁹)—, —CR¹⁹═CR²⁰—, —C≡C—, —C(O)O—,—C(O)S—, —OC(O)O—, C(O)NR¹⁹—, —CR¹⁹═N—, —CR¹⁹═NNH—, —NHC(O)O—,—NHC(O)NR¹⁹—, —NHCH₂NH—, —NHC(NH)CH₂C(NH)NH—, —CH(OH)CH₂(CO₂R¹⁹)—,—CH═CR¹⁹C(O)—, —C≡C—C≡C—, —C(CHR¹⁹R²⁰)S—,

—C(CH(CH₃)₂)Si(CH₃)₂—, —C(O)CH₂(CO₂R¹⁹)—,

and, an acrylate copolymer formed by reaction of a —OC(O)CH═CH₂ group oneach module and ethyl acrylate, wherein R¹⁹ and R²⁰ are independentlyselected from the group consisting of hydrogen, (1C-4C)alkyl and a groupthat confers a selected chemical or physical characteristic, or acombination thereof.
 48. The two-dimensional array of claim 47, whereinthe connector is separated from one or both of the modules bonded by theconnector by a spacer.
 49. The two-dimensional array of claim 48,wherein the spacer comprises a —(CH₂)_(n)— group, wherein n is 1-28.